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188 Publications visible to you, out of a total of 188
The Leipzig Health Atlas-An Open Platform to Present, Archive, and Share Biomedical Data, Analyses, and Models Online.
LHA - Leipzig Health Atlas

Abstract (Expand)

BACKGROUND: Clinical trials, epidemiological studies, clinical registries, and other prospective research projects, together with patient care services, are main sources of data in the medical research … domain. They serve often as a basis for secondary research in evidence-based medicine, prediction models for disease, and its progression. This data are often neither sufficiently described nor accessible. Related models are often not accessible as a functional program tool for interested users from the health care and biomedical domains. OBJECTIVE: The interdisciplinary project Leipzig Health Atlas (LHA) was developed to close this gap. LHA is an online platform that serves as a sustainable archive providing medical data, metadata, models, and novel phenotypes from clinical trials, epidemiological studies, and other medical research projects. METHODS: Data, models, and phenotypes are described by semantically rich metadata. The platform prefers to share data and models presented in original publications but is also open for nonpublished data. LHA provides and associates unique permanent identifiers for each dataset and model. Hence, the platform can be used to share prepared, quality-assured datasets and models while they are referenced in publications. All managed data, models, and phenotypes in LHA follow the FAIR principles, with public availability or restricted access for specific user groups. RESULTS: The LHA platform is in productive mode (https://www.health-atlas.de/). It is already used by a variety of clinical trial and research groups and is becoming increasingly popular also in the biomedical community. LHA is an integral part of the forthcoming initiative building a national research data infrastructure for health in Germany.

Authors: T. Kirsten, F. A. Meineke, H. Loeffler-Wirth, C. Beger, A. Uciteli, S. Staubert, M. Lobe, R. Hansel, F. G. Rauscher, J. Schuster, T. Peschel, H. Herre, J. Wagner, S. Zachariae, C. Engel, M. Scholz, E. Rahm, H. Binder, M. Loeffler

Date Published: 3rd Aug 2022

Publication Type: Journal article

On the Parametrization of Epidemiologic Models-Lessons from Modelling COVID-19 Epidemic.
Genetical Statistics and Systems Biology, Task Force COVID-19 Leipzig

Abstract (Expand)

Numerous prediction models of SARS-CoV-2 pandemic were proposed in the past. Unknown parameters of these models are often estimated based on observational data. However, lag in case-reporting, changing … testing policy or incompleteness of data lead to biased estimates. Moreover, parametrization is time-dependent due to changing age-structures, emerging virus variants, non-pharmaceutical interventions, and vaccination programs. To cover these aspects, we propose a principled approach to parametrize a SIR-type epidemiologic model by embedding it as a hidden layer into an input-output non-linear dynamical system (IO-NLDS). Observable data are coupled to hidden states of the model by appropriate data models considering possible biases of the data. This includes data issues such as known delays or biases in reporting. We estimate model parameters including their time-dependence by a Bayesian knowledge synthesis process considering parameter ranges derived from external studies as prior information. We applied this approach on a specific SIR-type model and data of Germany and Saxony demonstrating good prediction performances. Our approach can estimate and compare the relative effectiveness of non-pharmaceutical interventions and provide scenarios of the future course of the epidemic under specified conditions. It can be translated to other data sets, i.e., other countries and other SIR-type models.

Authors: Y. Kheifetz, H. Kirsten, M. Scholz

Date Published: 2nd Jul 2022

Publication Type: Journal article

Human Diseases: COVID-19

A biomathematical model of human erythropoiesis and iron metabolism
Genetical Statistics and Systems Biology

Abstract (Expand)

Anaemia therapy or perisurgical support of erythropoiesis often require both, EPO and iron medication. However, excessive iron medication can result in iron overload and it is challenging to control … haemoglobin levels in a desired range. To support this task, we develop a biomathematical model to simulate EPO- and iron medication in humans. We combine our previously established model of human erythropoiesis including comprehensive pharmacokinetic models of EPO applications with a newly developed model of iron metabolism including iron supplementation. Equations were derived by translating known biological mechanisms into ordinary differential equations. Qualitative model behaviour is studied in detail considering a variety of interventions such as bleeding, iron malnutrition and medication. The model can explain time courses of erythrocytes, reticulocytes, haemoglobin, haematocrit, red blood cells, EPO, serum iron, ferritin, transferrin saturation, and transferrin under a variety of scenarios including EPO and iron application into healthy volunteers or chemotherapy patients. Unknown model parameters were determined by fitting the predictions of the model to time series data from literature. We demonstrate how the model can be used to make predictions of untested therapy options such as cytotoxic chemotherapy supported by iron and EPO. Following our ultimate goal of establishing a model of anaemia treatment in chronic kidney disease, we aim at translating our model to this pathological condition in the near future.

Authors: Sibylle Schirm, Markus Scholz

Date Published: 1st Dec 2020

Publication Type: Journal article

Dynamics of cytokines, immune cell counts and disease severity in patients with community-acquired pneumonia - Unravelling potential causal relationships
Genetical Statistics and Systems Biology

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BACKGROUND Community acquired pneumonia (CAP) is a severe and often rapidly deteriorating disease. To better understand its dynamics and potential causal relationships, we analyzed time series data of …f cytokines, blood and clinical parameters in hospitalized CAP patients. METHODS Time series data of 10 circulating cytokines, blood counts and clinical parameters were related to baseline characteristics of 403 CAP patients using univariate mixed models. Bivariate mixed models were applied to analyze correlations between the time series. To identify potential causal relationships, we inferred cross-lagged relationships between pairs of parameters using latent curve models with structured residuals. RESULTS IL-6 levels decreased faster over time in younger patients (Padj = 0.06). IL-8, VCAM-1, and IL-6 correlated strongly with disease severity as assessed by the sequential organ failure assessment (SOFA) score (r = 0.49, 0.48, 0.46, respectively; all Padj \textless 0.001). IL-6 and bilirubin correlated with respect to their mean levels and slopes over time (r = 0.36 and r = 0.46, respectively; Padj \textless 0.001). A number of potential causal relationships were identified, e.g., a negative effect of ICAM-1 on MCP-1, or a positive effect of the level of creatinine on the subsequent VCAM-1 concentration (P \textless 0.001). CONCLUSIONS These results suggest that IL-6 trajectories of CAP patients are associated with age and run parallel to bilirubin levels. The time series analysis also unraveled directed, potentially causal relationships between cytokines, blood parameters and clinical outcomes. This will facilitate the development of mechanistic models of CAP, and with it, improvements in treatment or surveillance strategies for this disease. TRIAL REGISTRATION clinicaltrials.gov NCT02782013, May 25, 2016, retrospectively registered.

Authors: Maciej Rosolowski, Volker Oberle, Peter Ahnert, Petra Creutz, Martin Witzenrath, Michael Kiehntopf, Markus Loeffler, Norbert Suttorp, Markus Scholz

Date Published: 1st Dec 2020

Publication Type: Journal article

Integration of mathematical model predictions into routine workflows to support clinical decision making in haematology
Genetical Statistics and Systems Biology

Abstract (Expand)

BACKGROUND Individualization and patient-specific optimization of treatment is a major goal of modern health care. One way to achieve this goal is the application of high-resolution diagnostics together …r with the application of targeted therapies. However, the rising number of different treatment modalities also induces new challenges: Whereas randomized clinical trials focus on proving average treatment effects in specific groups of patients, direct conclusions at the individual patient level are problematic. Thus, the identification of the best patient-specific treatment options remains an open question. Systems medicine, specifically mechanistic mathematical models, can substantially support individual treatment optimization. In addition to providing a better general understanding of disease mechanisms and treatment effects, these models allow for an identification of patient-specific parameterizations and, therefore, provide individualized predictions for the effect of different treatment modalities. RESULTS In the following we describe a software framework that facilitates the integration of mathematical models and computer simulations into routine clinical processes to support decision-making. This is achieved by combining standard data management and data exploration tools, with the generation and visualization of mathematical model predictions for treatment options at an individual patient level. CONCLUSIONS By integrating model results in an audit trail compatible manner into established clinical workflows, our framework has the potential to foster the use of systems-medical approaches in clinical practice. We illustrate the framework application by two use cases from the field of haematological oncology.

Authors: Katja Hoffmann, Katja Cazemier, Christoph Baldow, Silvio Schuster, Yuri Kheifetz, Sibylle Schirm, Matthias Horn, Thomas Ernst, Constanze Volgmann, Christian Thiede, Andreas Hochhaus, Martin Bornhäuser, Meinolf Suttorp, Markus Scholz, Ingmar Glauche, Markus Loeffler, Ingo Roeder

Date Published: 1st Dec 2020

Publication Type: Journal article

Genome-wide association meta-analysis for early age-related macular degeneration highlights novel loci and insights for advanced disease
Genetical Statistics and Systems Biology

Abstract (Expand)

BACKGROUND Advanced age-related macular degeneration (AMD) is a leading cause of blindness. While around half of the genetic contribution to advanced AMD has been uncovered, little is known about the … genetic architecture of early AMD. METHODS To identify genetic factors for early AMD, we conducted a genome-wide association study (GWAS) meta-analysis (14,034 cases, 91,214 controls, 11 sources of data including the International AMD Genomics Consortium, IAMDGC, and UK Biobank, UKBB). We ascertained early AMD via color fundus photographs by manual grading for 10 sources and via an automated machine learning approach for > 170,000 photographs from UKBB. We searched for early AMD loci via GWAS and via a candidate approach based on 14 previously suggested early AMD variants. RESULTS Altogether, we identified 10 independent loci with statistical significance for early AMD: (i) 8 from our GWAS with genome-wide significance (P < 5 × 10- 8), (ii) one previously suggested locus with experiment-wise significance (P < 0.05/14) in our non-overlapping data and with genome-wide significance when combining the reported and our non-overlapping data (together 17,539 cases, 105,395 controls), and (iii) one further previously suggested locus with experiment-wise significance in our non-overlapping data. Of these 10 identified loci, 8 were novel and 2 known for early AMD. Most of the 10 loci overlapped with known advanced AMD loci (near ARMS2/HTRA1, CFH, C2, C3, CETP, TNFRSF10A, VEGFA, APOE), except two that have not yet been identified with statistical significance for any AMD. Among the 17 genes within these two loci, in-silico functional annotation suggested CD46 and TYR as the most likely responsible genes. Presence or absence of an early AMD effect distinguished the known pathways of advanced AMD genetics (complement/lipid pathways versus extracellular matrix metabolism). CONCLUSIONS Our GWAS on early AMD identified novel loci, highlighted shared and distinct genetics between early and advanced AMD and provides insights into AMD etiology. Our data provide a resource comparable in size to the existing IAMDGC data on advanced AMD genetics enabling a joint view. The biological relevance of this joint view is underscored by the ability of early AMD effects to differentiate the major pathways for advanced AMD.

Authors: Thomas W. Winkler, Felix Grassmann, Caroline Brandl, Christina Kiel, Felix Günther, Tobias Strunz, Lorraine Weidner, Martina E. Zimmermann, Christina A. Korb, Alicia Poplawski, Alexander K. Schuster, Martina Müller-Nurasyid, Annette Peters, Franziska G. Rauscher, Tobias Elze, Katrin Horn, Markus Scholz, Marisa Cañadas-Garre, Amy Jayne McKnight, Nicola Quinn, Ruth E. Hogg, Helmut Küchenhoff, Iris M. Heid, Klaus J. Stark, Bernhard H. F. Weber

Date Published: 1st Dec 2020

Publication Type: Journal article

Metabolite-Investigator: an integrated user-friendly workflow for metabolomics multi-study analysis
Genetical Statistics and Systems Biology

Abstract (Expand)

Motivation Many diseases have a metabolic background, which is increasingly investigated due to improved measurement techniques allowing high-throughput assessment of metabolic features in several body … fluids. Integrating data from multiple cohorts is of high importance to obtain robust and reproducible results. However, considerable variability across studies due to differences in sampling, measurement techniques and study populations needs to be accounted for. Results We present Metabolite-Investigator, a scalable analysis workflow for quantitative metabolomics data from multiple studies. Our tool supports all aspects of data pre-processing including data integration, cleaning, transformation, batch analysis as well as multiple analysis methods including uni- and multivariable factor-metabolite associations, network analysis and factor prioritization in one or more cohorts. Moreover, it allows identifying critical interactions between cohorts and factors affecting metabolite levels and inferring a common covariate model, all via a graphical user interface. Availability and implementation We constructed Metabolite-Investigator as a free and open web-tool and stand-alone Shiny-app. It is hosted at https://apps.health-atlas.de/metabolite-investigator/, the source code is freely available at https://github.com/cfbeuchel/Metabolite-Investigator. Supplementary information Supplementary data are available at Bioinformatics online.

Authors: Carl Beuchel, Holger Kirsten, Uta Ceglarek, Markus Scholz

Date Published: 16th Nov 2020

Publication Type: Journal article

Meta-analysis uncovers genome-wide significant variants for rapid kidney function decline.
LIFE Adult, Genetical Statistics and Systems Biology, LIFE Heart

Abstract (Expand)

Rapid decline of glomerular filtration rate estimated from creatinine (eGFRcrea) is associated with severe clinical endpoints. In contrast to cross-sectionally assessed eGFRcrea, the genetic basis for … rapid eGFRcrea decline is largely unknown. To help define this, we meta-analyzed 42 genome-wide association studies from the Chronic Kidney Diseases Genetics Consortium and United Kingdom Biobank to identify genetic loci for rapid eGFRcrea decline. Two definitions of eGFRcrea decline were used: 3 mL/min/1.73m(2)/year or more ("Rapid3"; encompassing 34,874 cases, 107,090 controls) and eGFRcrea decline 25% or more and eGFRcrea under 60 mL/min/1.73m(2) at follow-up among those with eGFRcrea 60 mL/min/1.73m(2) or more at baseline ("CKDi25"; encompassing 19,901 cases, 175,244 controls). Seven independent variants were identified across six loci for Rapid3 and/or CKDi25: consisting of five variants at four loci with genome-wide significance (near UMOD-PDILT (2), PRKAG2, WDR72, OR2S2) and two variants among 265 known eGFRcrea variants (near GATM, LARP4B). All these loci were novel for Rapid3 and/or CKDi25 and our bioinformatic follow-up prioritized variants and genes underneath these loci. The OR2S2 locus is novel for any eGFRcrea trait including interesting candidates. For the five genome-wide significant lead variants, we found supporting effects for annual change in blood urea nitrogen or cystatin-based eGFR, but not for GATM or LARP4B. Individuals at high compared to those at low genetic risk (8-14 vs 0-5 adverse alleles) had a 1.20-fold increased risk of acute kidney injury (95% confidence interval 1.08-1.33). Thus, our identified loci for rapid kidney function decline may help prioritize therapeutic targets and identify mechanisms and individuals at risk for sustained deterioration of kidney function.

Authors: M. Gorski, B. Jung, Y. Li, P. R. Matias-Garcia, M. Wuttke, S. Coassin, C. H. L. Thio, M. E. Kleber, T. W. Winkler, V. Wanner, J. F. Chai, A. Y. Chu, M. Cocca, M. F. Feitosa, S. Ghasemi, A. Hoppmann, K. Horn, M. Li, T. Nutile, M. Scholz, K. B. Sieber, A. Teumer, A. Tin, J. Wang, B. O. Tayo, T. S. Ahluwalia, P. Almgren, S. J. L. Bakker, B. Banas, N. Bansal, M. L. Biggs, E. Boerwinkle, E. P. Bottinger, H. Brenner, R. J. Carroll, J. Chalmers, M. L. Chee, M. L. Chee, C. Y. Cheng, J. Coresh, M. H. de Borst, F. Degenhardt, K. U. Eckardt, K. Endlich, A. Franke, S. Freitag-Wolf, P. Gampawar, R. T. Gansevoort, M. Ghanbari, C. Gieger, P. Hamet, K. Ho, E. Hofer, B. Holleczek, V. H. Xian Foo, N. Hutri-Kahonen, S. J. Hwang, M. A. Ikram, N. S. Josyula, M. Kahonen, C. C. Khor, W. Koenig, H. Kramer, B. K. Kramer, B. Kuhnel, L. A. Lange, T. Lehtimaki, W. Lieb, R. J. F. Loos, M. A. Lukas, L. P. Lyytikainen, C. Meisinger, T. Meitinger, O. Melander, Y. Milaneschi, P. P. Mishra, N. Mononen, J. C. Mychaleckyj, G. N. Nadkarni, M. Nauck, K. Nikus, B. Ning, I. M. Nolte, M. L. O'Donoghue, M. Orho-Melander, S. A. Pendergrass, B. W. J. H. Penninx, M. H. Preuss, B. M. Psaty, L. M. Raffield, O. T. Raitakari, R. Rettig, M. Rheinberger, K. M. Rice, A. R. Rosenkranz, P. Rossing, J. I. Rotter, C. Sabanayagam, H. Schmidt, R. Schmidt, B. Schottker, C. A. Schulz, S. Sedaghat, C. M. Shaffer, K. Strauch, S. Szymczak, K. D. Taylor, J. Tremblay, L. Chaker, P. van der Harst, P. J. van der Most, N. Verweij, U. Volker, M. Waldenberger, L. Wallentin, D. M. Waterworth, H. D. White, J. G. Wilson, T. Y. Wong, M. Woodward, Q. Yang, M. Yasuda, L. M. Yerges-Armstrong, Y. Zhang, H. Snieder, C. Wanner, C. A. Boger, A. Kottgen, F. Kronenberg, C. Pattaro, I. M. Heid

Date Published: 30th Oct 2020

Publication Type: Journal article

Prevalence of atrial fibrillation dependent on coronary artery status: Insights from the LIFE-Heart Study.
Genetical Statistics and Systems Biology

Abstract (Expand)

BACKGROUND: Coronary artery disease (CAD) is a significant risk factor for atrial fibrillation (AF). Experimental studies demonstrated that atrial ischemia induced by right coronary artery (RCA) stenosis … promote AF triggers and development of electro-anatomical substrate for AF. AIM: To analyze the association between AF prevalence and coronary arteries status in the LIFE-Heart Study. METHODS: This analysis included patients with available coronary catheterization data recruited between 2006 and 2014. Patients with acute myocardial infarction were excluded. CAD was defined as stenosis >/=75%, while coronary artery sclerosis (CAS) was defined as non-critical plaque(s) <75%. RESULTS: In total, 3.458 patients (median age 63 years, 34% women) were included into analysis. AF was diagnosed in 238 (6.7%) patients. There were 681 (19.7%) patients with CAS and 1.411 (40.8%) with CAD (27.5% with single, 32.4% with double, and 40.1% with triple vessel CAD). In multivariable analysis, there was a significant association between prevalent AF and coronary artery status (OR 0.64, 95% CI 0.53-0.78, Ptrend < .001). Similarly, AF risk was lower in patients with higher CAD extent (OR 0.54, 95%CI 0.35-0.83, Ptrend = .005). Compared to single vessel CAD, the risk of AF was lower in double (OR 0.42, 95%CI 0.19-0.95, P = .037) and triple CAD (OR 0.31, 95%CI 0.13-0.71, P = .006). Finally, no association was found between AF prevalence and CAD origin among patients with single vessel CAD. CONCLUSION: In the LIFE-Heart Study, CAS but not CAD was associated with increased risk of AF.

Authors: J. Kornej, S. Henger, T. Seewoster, A. Teren, R. Burkhardt, H. Thiele, J. Thiery, M. Scholz

Date Published: 27th Oct 2020

Publication Type: Journal article

Higher BMI, but not obesity-related genetic polymorphisms, correlates with lower structural connectivity of the reward network in a population-based study.
Genetical Statistics and Systems Biology

Abstract (Expand)

BACKGROUND: Obesity is of complex origin, involving genetic and neurobehavioral factors. Genetic polymorphisms may increase the risk for developing obesity by modulating dopamine-dependent behaviors, … such as reward processing. Yet, few studies have investigated the association of obesity, related genetic variants, and structural connectivity of the dopaminergic reward network. METHODS: We analyzed 347 participants (age range: 20-59 years, BMI range: 17-38 kg/m(2)) of the LIFE-Adult Study. Genotyping for the single nucleotid polymorphisms rs1558902 (FTO) and rs1800497 (near dopamine D2 receptor) was performed on a microarray. Structural connectivity of the reward network was derived from diffusion-weighted magnetic resonance imaging at 3 T using deterministic tractography of Freesurfer-derived regions of interest. Using graph metrics, we extracted summary measures of clustering coefficient and connectivity strength between frontal and striatal brain regions. We used linear models to test the association of BMI, risk alleles of both variants, and reward network connectivity. RESULTS: Higher BMI was significantly associated with lower connectivity strength for number of streamlines (beta = -0.0025, 95%-C.I.: [-0.004, -0.0008], p = 0.0042), and, to lesser degree, fractional anisotropy (beta = -0.0009, 95%-C.I. [-0.0016, -0.00008], p = 0.031), but not clustering coefficient. Strongest associations were found for left putamen, right accumbens, and right lateral orbitofrontal cortex. As expected, the polymorphism rs1558902 in FTO was associated with higher BMI (F = 6.9, p < 0.001). None of the genetic variants was associated with reward network structural connectivity. CONCLUSIONS: Here, we provide evidence that higher BMI correlates with lower reward network structural connectivity. This result is in line with previous findings of obesity-related decline in white matter microstructure. We did not observe an association of variants in FTO or near DRD2 receptor with reward network structural connectivity in this population-based cohort with a wide range of BMI and age. Future research should further investigate the link between genetics, obesity and fronto-striatal structural connectivity.

Authors: F. Beyer, R. Zhang, M. Scholz, K. Wirkner, M. Loeffler, M. Stumvoll, A. Villringer, A. V. Witte

Date Published: 25th Oct 2020

Publication Type: Journal article

The Obesity-Susceptibility Gene TMEM18 Promotes Adipogenesis through Activation of PPARG.
Genetical Statistics and Systems Biology

Abstract (Expand)

TMEM18 is the strongest candidate for childhood obesity identified from GWASs, yet as for most GWAS-derived obesity-susceptibility genes, the functional mechanism remains elusive. We here investigate … the relevance of TMEM18 for adipose tissue development and obesity. We demonstrate that adipocyte TMEM18 expression is downregulated in children with obesity. Functionally, downregulation of TMEM18 impairs adipocyte formation in zebrafish and in human preadipocytes, indicating that TMEM18 is important for adipocyte differentiation in vivo and in vitro. On the molecular level, TMEM18 activates PPARG, particularly upregulating PPARG1 promoter activity, and this activation is repressed by inflammatory stimuli. The relationship between TMEM18 and PPARG1 is also evident in adipocytes of children and is clinically associated with obesity and adipocyte hypertrophy, inflammation, and insulin resistance. Our findings indicate a role of TMEM18 as an upstream regulator of PPARG signaling driving healthy adipogenesis, which is dysregulated with adipose tissue dysfunction and obesity.

Authors: K. Landgraf, N. Kloting, M. Gericke, N. Maixner, E. Guiu-Jurado, M. Scholz, A. V. Witte, F. Beyer, J. T. Schwartze, M. Lacher, A. Villringer, P. Kovacs, A. Rudich, M. Bluher, W. Kiess, A. Korner

Date Published: 20th Oct 2020

Publication Type: Journal article

Novel loci for childhood body mass index and shared heritability with adult cardiometabolic traits.
Genetical Statistics and Systems Biology

Abstract (Expand)

The genetic background of childhood body mass index (BMI), and the extent to which the well-known associations of childhood BMI with adult diseases are explained by shared genetic factors, are largely … unknown. We performed a genome-wide association study meta-analysis of BMI in 61,111 children aged between 2 and 10 years. Twenty-five independent loci reached genome-wide significance in the combined discovery and replication analyses. Two of these, located near NEDD4L and SLC45A3, have not previously been reported in relation to either childhood or adult BMI. Positive genetic correlations of childhood BMI with birth weight and adult BMI, waist-to-hip ratio, diastolic blood pressure and type 2 diabetes were detected (Rg ranging from 0.11 to 0.76, P-values <0.002). A negative genetic correlation of childhood BMI with age at menarche was observed. Our results suggest that the biological processes underlying childhood BMI largely, but not completely, overlap with those underlying adult BMI. The well-known observational associations of BMI in childhood with cardio-metabolic diseases in adulthood may reflect partial genetic overlap, but in light of previous evidence, it is also likely that they are explained through phenotypic continuity of BMI from childhood into adulthood.

Authors: S. Vogelezang, J. P. Bradfield, T. S. Ahluwalia, J. A. Curtin, T. A. Lakka, N. Grarup, M. Scholz, P. J. van der Most, C. Monnereau, E. Stergiakouli, A. Heiskala, M. Horikoshi, I. O. Fedko, N. Vilor-Tejedor, D. L. Cousminer, M. Standl, C. A. Wang, J. Viikari, F. Geller, C. Iniguez, N. Pitkanen, A. Chesi, J. Bacelis, L. Yengo, M. Torrent, I. Ntalla, O. Helgeland, S. Selzam, J. M. Vonk, M. H. Zafarmand, B. Heude, I. S. Farooqi, A. Alyass, R. N. Beaumont, C. T. Have, P. Rzehak, J. R. Bilbao, T. M. Schnurr, I. Barroso, K. Bonnelykke, L. J. Beilin, L. Carstensen, M. A. Charles, B. Chawes, K. Clement, R. Closa-Monasterolo, A. Custovic, J. G. Eriksson, J. Escribano, M. Groen-Blokhuis, V. Grote, D. Gruszfeld, H. Hakonarson, T. Hansen, A. T. Hattersley, M. Hollensted, J. J. Hottenga, E. Hypponen, S. Johansson, R. Joro, M. Kahonen, V. Karhunen, W. Kiess, B. A. Knight, B. Koletzko, A. Kuhnapfel, K. Landgraf, J. P. Langhendries, T. Lehtimaki, J. T. Leinonen, A. Li, V. Lindi, E. Lowry, M. Bustamante, C. Medina-Gomez, M. Melbye, K. F. Michaelsen, C. S. Morgen, T. A. Mori, T. R. H. Nielsen, H. Niinikoski, A. J. Oldehinkel, K. Pahkala, K. Panoutsopoulou, O. Pedersen, C. E. Pennell, C. Power, S. A. Reijneveld, F. Rivadeneira, A. Simpson, P. D. Sly, J. Stokholm, K. K. Teo, E. Thiering, N. J. Timpson, A. G. Uitterlinden, C. E. M. van Beijsterveldt, B. D. C. van Schaik, M. Vaudel, E. Verduci, R. K. Vinding, M. Vogel, E. Zeggini, S. Sebert, M. V. Lind, C. D. Brown, L. Santa-Marina, E. Reischl, C. Frithioff-Bojsoe, D. Meyre, E. Wheeler, K. Ong, E. A. Nohr, T. G. M. Vrijkotte, G. H. Koppelman, R. Plomin, P. R. Njolstad, G. D. Dedoussis, P. Froguel, T. I. A. Sorensen, B. Jacobsson, R. M. Freathy, B. S. Zemel, O. Raitakari, M. Vrijheid, B. Feenstra, L. P. Lyytikainen, H. Snieder, H. Kirsten, P. G. Holt, J. Heinrich, E. Widen, J. Sunyer, D. I. Boomsma, M. R. Jarvelin, A. Korner, G. Davey Smith, J. C. Holm, M. Atalay, C. Murray, H. Bisgaard, M. I. McCarthy, V. W. V. Jaddoe, S. F. A. Grant, J. F. Felix

Date Published: 13th Oct 2020

Publication Type: Journal article

Transcriptomic Research in Heart Failure with Preserved Ejection Fraction: Current State and Future Perspectives.
Genetical Statistics and Systems Biology

Abstract (Expand)

Heart failure with preserved ejection fraction (HFpEF) is increasing in incidence and has a higher prevalence compared with heart failure with reduced ejection fraction. So far, no effective treatment … of HFpEF is available, due to its complex underlying pathophysiology and clinical heterogeneity. This article aims to provide an overview and a future perspective of transcriptomic biomarker research in HFpEF. Detailed characterisation of the HFpEF phenotype and its underlying molecular pathomechanisms may open new perspectives regarding early diagnosis, improved prognostication, new therapeutic targets and tailored therapies accounting for patient heterogeneity, which may improve quality of life. A combination of cross-sectional and longitudinal study designs with sufficiently large sample sizes are required to support this concept.

Authors: S. Rosch, K. P. Rommel, M. Scholz, H. Thiele, P. Lurz

Date Published: 12th Oct 2020

Publication Type: Journal article

Genetic correlations and genome-wide associations of cortical structure in general population samples of 22,824 adults.
Genetical Statistics and Systems Biology

Abstract (Expand)

Cortical thickness, surface area and volumes vary with age and cognitive function, and in neurological and psychiatric diseases. Here we report heritability, genetic correlations and genome-wide … associations of these cortical measures across the whole cortex, and in 34 anatomically predefined regions. Our discovery sample comprises 22,824 individuals from 20 cohorts within the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium and the UK Biobank. We identify genetic heterogeneity between cortical measures and brain regions, and 160 genome-wide significant associations pointing to wnt/beta-catenin, TGF-beta and sonic hedgehog pathways. There is enrichment for genes involved in anthropometric traits, hindbrain development, vascular and neurodegenerative disease and psychiatric conditions. These data are a rich resource for studies of the biological mechanisms behind cortical development and aging.

Authors: E. Hofer, G. V. Roshchupkin, H. H. H. Adams, M. J. Knol, H. Lin, S. Li, H. Zare, S. Ahmad, N. J. Armstrong, C. L. Satizabal, M. Bernard, J. C. Bis, N. A. Gillespie, M. Luciano, A. Mishra, M. Scholz, A. Teumer, R. Xia, X. Jian, T. H. Mosley, Y. Saba, L. Pirpamer, S. Seiler, J. T. Becker, O. Carmichael, J. I. Rotter, B. M. Psaty, O. L. Lopez, N. Amin, S. J. van der Lee, Q. Yang, J. J. Himali, P. Maillard, A. S. Beiser, C. DeCarli, S. Karama, L. Lewis, M. Harris, M. E. Bastin, I. J. Deary, A. Veronica Witte, F. Beyer, M. Loeffler, K. A. Mather, P. R. Schofield, A. Thalamuthu, J. B. Kwok, M. J. Wright, D. Ames, J. Trollor, J. Jiang, H. Brodaty, W. Wen, M. W. Vernooij, A. Hofman, A. G. Uitterlinden, W. J. Niessen, K. Wittfeld, R. Bulow, U. Volker, Z. Pausova, G. Bruce Pike, S. Maingault, F. Crivello, C. Tzourio, P. Amouyel, B. Mazoyer, M. C. Neale, C. E. Franz, M. J. Lyons, M. S. Panizzon, O. A. Andreassen, A. M. Dale, M. Logue, K. L. Grasby, N. Jahanshad, J. N. Painter, L. Colodro-Conde, J. Bralten, D. P. Hibar, P. A. Lind, F. Pizzagalli, J. L. Stein, P. M. Thompson, S. E. Medland, P. S. Sachdev, W. S. Kremen, J. M. Wardlaw, A. Villringer, C. M. van Duijn, H. J. Grabe, W. T. Jr Longstreth, M. Fornage, T. Paus, S. Debette, M. Arfan Ikram, H. Schmidt, R. Schmidt, S. Seshadri

Date Published: 22nd Sep 2020

Publication Type: Journal article

Pro-Neurotensin depends on renal function and is related to all-cause mortality in chronic kidney disease
Genetical Statistics and Systems Biology

Abstract (Expand)

BACKGROUND Patients with chronic kidney disease (CKD) have a high risk of premature cardiovascular diseases (CVD) and show increased mortality. Pro-Neurotensin (NT) was associated with metabolic diseases …s and predicted incident CVD and mortality. However, Pro-NT regulation in CKD and its potential role linking CKD and mortality have not been investigated, so far. METHODS In a central lab, circulating Pro-NT was quantified in three independent cohorts comprising 4,715 participants (cohort 1: patients with CKD; cohort 2: general population study; cohort 3: non-diabetic population study). Urinary Pro-NT was assessed in part of the patients from cohort 1. Serum Pro-NT was further related to mortality in patients with advanced CKD. Tissue-specific Nts expression was investigated in two mouse models of diabetic CKD and compared to non-diabetic control mice. RESULTS Pro-NT significantly increased with deteriorating renal function (p\textless0.001). In meta-analysis of cohorts 1-3, Pro-NT was significantly and independently associated with estimated glomerular filtration rate (p\leq0.002). Patients in the middle/high Pro-NT tertiles at baseline had a higher all-cause mortality compared to the low Pro-NT tertile (Hazard ratio: 2.11, p=0.046). Mice with severe diabetic CKD did not show increased Nts mRNA expression in different tissues compared to control animals. CONCLUSIONS Circulating Pro-NT is associated with impaired renal function in independent cohorts comprising 4,715 subjects and is related to all-cause mortality in patients with end-stage kidney disease. Our human and rodent data are in accordance with the hypotheses that Pro-NT is eliminated by the kidneys and could potentially contribute to increased mortality observed in patients with CKD.

Authors: Anke Toenjes, Annett Hoffmann, Susan Kralisch, Abdul Rashid Qureshi, Nora Klöting, Markus Scholz, Dorit Schleinitz, Anette Bachmann, Juergen Kratzsch, Marcin Nowicki, Sabine Paeschke, Kerstin Wirkner, Cornelia Enzenbach, Ronny Baber, Joachim Beige, Matthias Anders, Ingolf Bast, Matthias Blüher, Peter Kovacs, Markus Löffler, Ming-Zhi Zhang, Raymond C. Harris, Peter Stenvinkel, Michael Stumvoll, Mathias Fasshauer, Thomas Ebert

Date Published: 1st Sep 2020

Publication Type: Journal article

Relationship between fermented dairy consumption, circulating short-chain acylcarnitines and angiographic severity of coronary artery disease
Genetical Statistics and Systems Biology

Abstract (Expand)

BACKGROUND AND AIMS Current epidemiologic data suggest beneficial cardiovascular effects of fermented dairy products (FDP). However, the relationship between FDP consumption and angiographic coronary …y status has not been previously studied. Furthermore, the role of novel metabolomic biomarkers of cardiovascular risk in this context is unclear. We hypothesize that short-chain acylcarnitines (SCA) reflect the link between FDP intake and angiographic extent of stable coronary artery disease (CAD). METHODS AND RESULTS We recruited 1185 patients admitted for suspected CAD [median age 62 years (interquartile range: 54-69); 714 men (60.3%)]. Prior to coronary angiography, each patient completed a validated Food Frequency Questionnaire. In addition, venous blood was collected from each patient for whole blood metabolomic analysis, using targeted mass-spectrometry. CAD was defined by the presence of \geq1 coronary stenosis \geq50%. Patients with CAD (n = 441) reported lower median FDP intake [86.8 g/day (IQR: 53.4-127.6)] than patients without CAD [n = 744; 103.9 g/day (IQR: 62.9-152.7); p \textless 0.001]. Upon adjustment for relevant confounders, increased circulating SCA, particularly level of acetylcarnitine (C2) associated with both higher CAD probability [SCA:\textgreekb(SE) = 0.584 (0.235), p = 0.013; C2:\textgreekb(SE) = 0.575 (0.242), p = 0.017] and decreased FDP consumption [SCA:\textgreekb/100 g FDP-increment/day (SE) = -0.785 (0.242), p = 0.001; C2:\textgreekb(SE) = -0.560 (0.230), p = 0.015]. By mediation analysis, neither SCA nor C2 showed relevant mediator effect linking FDP consumption to the risk of CAD. CONCLUSION Increased consumption of fermented milk was associated with lower prevalence of CAD and correlated inversely with circulating SCA, in particular with acetylcarnitine. No substantial mediator effect of SCA linking fermented milk intake with risk of CAD was found. CLINICAL TRIAL REGISTRY NCT00497887.

Authors: Andrej Teren, Anika Vogel, Frank Beutner, Stephan Gielen, Ralph Burkhardt, Markus Scholz, Joachim Thiery, Uta Ceglarek

Date Published: 1st Sep 2020

Publication Type: Journal article

Genome-wide association analysis of pulse wave velocity traits provide new insights into the causal relationship between arterial stiffness and blood pressure
LIFE Adult

Abstract (Expand)

Background The pathophysiology of arterial stiffness is not completely understood. Pulse wave velocity (PWV) is an established marker for arterial stiffness. We compare genetics of three PWV modes, … namely carotid-femoral PWV (cfPWV), brachial-ankle (baPWV) and brachial-femoral (bfPWV), reflecting different vascular segments to analyse association with genetic variants, heritability and genetic correlation with other biological traits. Furthermore we searched for shared genetic architecture concerning PWV, blood pressure (BP) and coronary artery disease (CAD) and examined the causal relationship between PWV and BP. Methods and results We performed a genome-wide association study (GWAS) for cfPWV, baPWV and bfPWV in LIFE-Adult (N = 3,643–6,734). We analysed the overlap of detected genetic loci with those of BP and CAD and performed genetic correlation analyses. By bidirectional Mendelian Randomization, we assessed the causal relationships between PWV and BP. For cfPWV we identified a new locus with genome-wide significance near SLC4A7 on cytoband 3p24.1 (lead SNP rs939834: p = 2.05x10-8). We replicated a known PWV locus on cytoband 14q32.2 near RP11-61O1.1 (lead SNPs: rs17773233, p = 1.38x10-4; rs1381289, p = 1.91x10-4) For baPWV we estimated a heritability of 28% and significant genetic correlation with hypertension (rg = 0.27, p = 6.65x10-8). We showed a positive causal effect of systolic blood pressure on PWV modes (cfPWV: p = 1.51x10-4; bfPWV: p = 1.45x10-3; baPWV: p = 6.82x10-15). Conclusions We identified a new locus for arterial stiffness and successfully replicated an earlier proposed locus. PWV shares common genetic architecture with BP and CAD. BP causally affects PWV. Larger studies are required to further unravel the genetic determinants and effects of PWV.

Authors: Michael Rode, Andrej Teren, Kerstin Wirkner, Katrin Horn, Holger Kirsten, Markus Loeffler, Markus Scholz, Janne Pott

Date Published: 13th Aug 2020

Publication Type: Journal article

Human Diseases: arteriosclerosis, arteriosclerotic cardiovascular disease

Association of Factor V Leiden With Subsequent Atherothrombotic Events: A GENIUS-CHD Study of Individual Participant Data.
Genetical Statistics and Systems Biology

Abstract (Expand)

Background: Studies examining the role of factor V Leiden among patients at higher risk of atherothrombotic events, such as those with established coronary heart disease (CHD) are lacking. Given that … coagulation is involved in the thrombus formation stage upon atherosclerotic plaque rupture, we hypothesized that factor V Leiden may be a stronger risk factor for atherothrombotic events in patients with established CHD. Methods: We performed an individual-level meta-analysis including 25 prospective studies (18 cohorts, 3 case-cohorts, 4 randomized trials) from the GENIUS-CHD consortium involving patients with established CHD at baseline. Participating studies genotyped factor V Leiden status and shared risk estimates for the outcomes of interest using a centrally developed statistical code with harmonized definitions across studies. Cox-regression models were used to obtain age and sex adjusted estimates. The obtained estimates were pooled using fixed-effect meta-analysis. The primary outcome was composite of myocardial infarction and CHD death. Secondary outcomes included any stroke, ischemic stroke, coronary revascularization, cardiovascular mortality and all-cause mortality. Results: The studies included 69,681 individuals of whom 3,190 (4.6%) were either heterozygous or homozygous (n=47) carriers of factor V Leiden. Median follow-up per study ranged from 1.0 to 10.6 years. A total of 20 studies with 61,147 participants and 6,849 events contributed to analyses of the primary outcome. Factor V Leiden was not associated with the combined outcome of myocardial infarction and CHD death (hazard ratio, 1.03; 95% CI, 0.92 - 1.16; I2 = 28%; P-heterogeneity = 0.12). Subgroup analysis according to baseline characteristics or strata of traditional cardiovascular risk factors did not show relevant differences. Similarly, risk estimates for the secondary outcomes including stroke, coronary revascularization, cardiovascular mortality and all-cause mortality were close to identity. Conclusions: Factor V Leiden was not associated with increased risk of subsequent atherothrombotic events and mortality in high-risk participants with established and treated CHD. Routine assessment of factor V Leiden status is unlikely to improve atherothrombotic events risk stratification in this population.

Authors: Bakhtawar K. Mahmoodi, Vinicius Tragante, Marcus E. Kleber, Michael V. Holmes, Amand F. Schmidt, Raymond O. McCubrey, Laurence J. Howe, Kenan Direk, Hooman Allayee, Ekaterina V. Baranova, Peter S. Braund, Graciela E. Delgado, Niclas Eriksson, Crystel M. Gijsberts, Yan Gong, Jaana Hartiala, Mahyar Heydarpour, Gerard Pasterkamp, Salma Kotti, Pekka Kuukasjärvi, Petra A. Lenzini, Daniel Levin, Leo-Pekka Lyytikäinen, Jochen D. Muehlschlegel, Christopher P. Nelson, Kjell Nikus, Anna P. Pilbrow, W. H. Wilson Tang, Sander W. van der Laan, Jessica van Setten, Ragnar O. Vilmundarson, John Deanfield, Panos Deloukas, Frank Dudbridge, Stefan James, Ify R. Mordi, Andrej Teren, Thomas O. Bergmeijer, Simon C. Body, Michiel Bots, Ralph Burkhardt, Rhonda M. Cooper-DeHoff, Sharon Cresci, Nicolas Danchin, Robert N. Doughty, Diederick E. Grobbee, Emil Hagström, Stanley L. Hazen, Claes Held, Imo E. Hoefer, G. Kees Hovingh, Julie A. Johnson, Marcin P. Kaczor, Mika Kähönen, Olaf H. Klungel, Jari O. Laurikka, Terho Lehtimäki, Anke H. Maitland-van der Zee, Ruth McPherson, Colin N. Palmer, Adriaan O. Kraaijeveld, Carl J. Pepine, Marek Sanak, Naveed Sattar, Markus Scholz, Tabassome Simon, John A. Spertus, Alexandre F. R. Stewart, Wojciech Szczeklik, Joachim Thiery, Frank L. J. Visseren, Johannes Waltenberger, A. Mark Richards, Chim C. Lang, Vicky A. Cameron, Axel Åkerblom, Guillaume Pare, Winfried März, Nilesh J. Samani, Aroon D. Hingorani, Jurriën M. ten Berg, Lars Wallentin, Folkert W. Asselbergs, Riyaz Patel

Date Published: 11th Aug 2020

Publication Type: Journal article

Cohort profile: The Leipzig Research Center for Civilization Diseases–Heart study (LIFE-Heart)
Genetical Statistics and Systems Biology

Abstract

Not specified

Authors: Markus Scholz, Sylvia Henger, Frank Beutner, Andrej Teren, Ronny Baber, Anja Willenberg, Uta Ceglarek, Janne Pott, Ralph Burkhardt, Joachim Thiery

Date Published: 3rd Aug 2020

Publication Type: Journal article

Genetically programmed changes in transcription of the novel progranulin regulator
Genetical Statistics and Systems Biology

Abstract (Expand)

Progranulin is a glycoprotein marking chronic inflammation in obesity and type 2 diabetes. Previous studies suggested PSRC1 (proline and serine rich coiled-coil 1) to be a target of genetic variants … associated with serum progranulin levels. We aimed to identify potentially functional variants and characterize their role in regulation of PSRC1. Phylogenetic module complexity analysis (PMCA) prioritized four polymorphisms (rs12740374, rs629301, rs660240, rs7528419) altering transcription factor binding sites with an overall score for potential regulatory function of Sall \textgreater 7.0. The effects of these variants on transcriptional activity and binding of transcription factors were tested by luciferase reporter and electrophoretic mobility shift assays (EMSA). In parallel, blood DNA promoter methylation of two regions was tested in subjects with a very high (N = 100) or a very low (N = 100) serum progranulin. Luciferase assays revealed lower activities in vectors carrying the rs629301-A compared with the C allele. Moreover, EMSA indicated a different binding pattern for the two rs629301 alleles, with an additional prominent band for the A allele, which was finally confirmed with the supershift for the Yin Yang 1 transcription factor (YY1). Subjects with high progranulin levels manifested a significantly higher mean DNA methylation (P \textless 1 \times 10-7) in one promoter region, which was in line with a significantly lower PSRC1 mRNA expression levels in blood (P = 1 \times 10-3). Consistently, rs629301-A allele was associated with lower PSRC1 mRNA expression (P \textless 1 \times 10-7). Our data suggest that the progranulin-associated variant rs629301 modifies the transcription of PSRC1 through alteration of YY1 binding capacity. DNA methylation studies further support the role of PSRC1 in regulation of progranulin serum levels. KEY MESSAGES: PSRC1 (proline and serine rich coiled-coil 1) SNPs are associated with serum progranulin levels. rs629301 regulates PSRC1 expression by affecting Yin Yang 1 transcription factor (YY1) binding. PSRC1 is also epigenetically regulated in subjects with high progranulin levels.

Authors: Maria Keller, Claudia Gebhardt, Sandra Huth, Dorit Schleinitz, Henrike Heyne, Markus Scholz, Michael Stumvoll, Yvonne Böttcher, Anke Tönjes, Peter Kovacs

Date Published: 1st Aug 2020

Publication Type: Journal article

Analysis of GPRC6A variants in different pancreatitis etiologies
Genetical Statistics and Systems Biology

Abstract (Expand)

BACKGROUND The G-protein-coupled receptor Class C Group 6 Member A (GPRC6A) is activated by multiple ligands and is important for the regulation of calcium homeostasis. Extracellular calcium is capable …e to increase NLRP3 inflammasome activity of the innate immune system and deletion of this proinflammatory pathway mitigated pancreatitis severity in vivo. As such this pathway and the GPRC6A receptor is a reasonable candidate gene for pancreatitis. Here we investigated the prevalence of sequence variants in the GPRC6A locus in different pancreatitis aetiologies. METHODS We selected 6 tagging SNPs with the SNPinfo LD TAG SNP Selection tool and the functional relevant SNP rs6907580 for genotyping. Cohorts from Germany, further European countries and China with up to 1,124 patients and 1,999 controls were screened for single SNPs with melting curve analysis. RESULTS We identified an association of rs1606365(G) with alcoholic chronic pancreatitis in a German (odds ratio (OR) 0.76, 95% confidence interval (CI) 0.65-0.89, p = 8 \times 10-5) and a Chinese cohort (OR 0.78, 95% CI 0.64-0.96, p = 0.02). However, this association was not replicated in a combined cohort of European patients (OR 1.18, 95% CI 0.99-1.41, p = 0.07). Finally, no association was found with acute and non-alcoholic chronic pancreatitis. CONCLUSIONS Our results support a potential role of calcium sensing receptors and inflammasome activation in alcoholic chronic pancreatitis development. As the functional consequence of the associated variant is unclear, further investigations might elucidate the relevant mechanisms.

Authors: Tom Kaune, Claudia Ruffert, Nico Hesselbarth, Marko Damm, Sebastian Krug, Julian Cardinal von Widdern, Emmanuelle Masson, Jian-Min Chen, Vinciane Rebours, Louis Buscail, Claude Férec, Robert Grützmann, Rene H. M. Te Morsche, Joost Ph Drenth, Giulia Martina Cavestro, Raffaella Alessia Zuppardo, Adrian Saftoiu, Ewa Malecka-Panas, Stanislaw Głuszek, Peter Bugert, Markus M. Lerch, Matthias Sendler, Frank Ulrich Weiss, Wen-Bin Zou, Shun-Jiang Deng, Zhuan Liao, Markus Scholz, Holger Kirsten, Peter Hegyi, Heiko Witt, Patrick Michl, Heidi Griesmann, Jonas Rosendahl

Date Published: 1st Aug 2020

Publication Type: Journal article

Common Genetic Variation Indicates Separate Causes for Periventricular and Deep White Matter Hyperintensities
Genetical Statistics and Systems Biology

Abstract (Expand)

BACKGROUND AND PURPOSE Periventricular white matter hyperintensities (WMH; PVWMH) and deep WMH (DWMH) are regional classifications of WMH and reflect proposed differences in cause. In the first study, …, to date, we undertook genome-wide association analyses of DWMH and PVWMH to show that these phenotypes have different genetic underpinnings. METHODS Participants were aged 45 years and older, free of stroke and dementia. We conducted genome-wide association analyses of PVWMH and DWMH in 26,654 participants from CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology), ENIGMA (Enhancing Neuro-Imaging Genetics Through Meta-Analysis), and the UKB (UK Biobank). Regional correlations were investigated using the genome-wide association analyses -pairwise method. Cross-trait genetic correlations between PVWMH, DWMH, stroke, and dementia were estimated using LDSC. RESULTS In the discovery and replication analysis, for PVWMH only, we found associations on chromosomes 2 (NBEAL), 10q23.1 (TSPAN14/FAM231A), and 10q24.33 (SH3PXD2A). In the much larger combined meta-analysis of all cohorts, we identified ten significant regions for PVWMH: chromosomes 2 (3 regions), 6, 7, 10 (2 regions), 13, 16, and 17q23.1. New loci of interest include 7q36.1 (NOS3) and 16q24.2. In both the discovery/replication and combined analysis, we found genome-wide significant associations for the 17q25.1 locus for both DWMH and PVWMH. Using gene-based association analysis, 19 genes across all regions were identified for PVWMH only, including the new genes: CALCRL (2q32.1), KLHL24 (3q27.1), VCAN (5q27.1), and POLR2F (22q13.1). Thirteen genes in the 17q25.1 locus were significant for both phenotypes. More extensive genetic correlations were observed for PVWMH with small vessel ischemic stroke. There were no associations with dementia for either phenotype. CONCLUSIONS Our study confirms these phenotypes have distinct and also shared genetic architectures. Genetic analyses indicated PVWMH was more associated with ischemic stroke whilst DWMH loci were implicated in vascular, astrocyte, and neuronal function. Our study confirms these phenotypes are distinct neuroimaging classifications and identifies new candidate genes associated with PVWMH only.

Authors: Nicola J. Armstrong, Karen A. Mather, Muralidharan Sargurupremraj, Maria J. Knol, Rainer Malik, Claudia L. Satizabal, Lisa R. Yanek, Wei Wen, Vilmundur G. Gudnason, Nicole D. Dueker, Lloyd T. Elliott, Edith Hofer, Joshua Bis, Neda Jahanshad, Shuo Li, Mark A. Logue, Michelle Luciano, Markus Scholz, Albert V. Smith, Stella Trompet, Dina Vojinovic, Rui Xia, Fidel Alfaro-Almagro, David Ames, Najaf Amin, Philippe Amouyel, Alexa S. Beiser, Henry Brodaty, Ian J. Deary, Christine Fennema-Notestine, Piyush G. Gampawar, Rebecca Gottesman, Ludovica Griffanti, Clifford R. Jack, Mark Jenkinson, Jiyang Jiang, Brian G. Kral, John B. Kwok, Leonie Lampe, David C M Liewald, Pauline Maillard, Jonathan Marchini, Mark E. Bastin, Bernard Mazoyer, Lukas Pirpamer, José Rafael Romero, Gennady V. Roshchupkin, Peter R. Schofield, Matthias L. Schroeter, David J. Stott, Anbupalam Thalamuthu, Julian Trollor, Christophe Tzourio, Jeroen van der Grond, Meike W. Vernooij, Veronica A. Witte, Margaret J. Wright, Qiong Yang, Zoe Morris, Siggi Siggurdsson, Bruce Psaty, Arno Villringer, Helena Schmidt, Asta K. Haberg, Cornelia M. van Duijn, J. Wouter Jukema, Martin Dichgans, Ralph L. Sacco, Clinton B. Wright, William S. Kremen, Lewis C. Becker, Paul M. Thompson, Thomas H. Mosley, Joanna M. Wardlaw, M. Arfan Ikram, Hieab H. H. Adams, Sudha Seshadri, Perminder S. Sachdev, Stephen M. Smith, Lenore Launer, William Longstreth, Charles DeCarli, Reinhold Schmidt, Myriam Fornage, Stephanie Debette, Paul A. Nyquist

Date Published: 1st Jul 2020

Publication Type: Journal article

Global and Regional Development of the Human Cerebral Cortex: Molecular Architecture and Occupational Aptitudes.
Genetical Statistics and Systems Biology

Abstract (Expand)

We have carried out meta-analyses of genome-wide association studies (GWAS) (n = 23 784) of the first two principal components (PCs) that group together cortical regions with shared variance in their … surface area. PC1 (global) captured variations of most regions, whereas PC2 (visual) was specific to the primary and secondary visual cortices. We identified a total of 18 (PC1) and 17 (PC2) independent loci, which were replicated in another 25 746 individuals. The loci of the global PC1 included those associated previously with intracranial volume and/or general cognitive function, such as MAPT and IGF2BP1. The loci of the visual PC2 included DAAM1, a key player in the planar-cell-polarity pathway. We then tested associations with occupational aptitudes and, as predicted, found that the global PC1 was associated with General Learning Ability, and the visual PC2 was associated with the Form Perception aptitude. These results suggest that interindividual variations in global and regional development of the human cerebral cortex (and its molecular architecture) cascade-albeit in a very limited manner-to behaviors as complex as the choice of one’s occupation.

Authors: Jean Shin, Shaojie Ma, Edith Hofer, Yash Patel, Daniel E. Vosberg, Steven Tilley, Gennady V. Roshchupkin, André M. M. Sousa, Xueqiu Jian, Rebecca Gottesman, Thomas H. Mosley, Myriam Fornage, Yasaman Saba, Lukas Pirpamer, Reinhold Schmidt, Helena Schmidt, Amaia Carrion-Castillo, Fabrice Crivello, Bernard Mazoyer, Joshua C. Bis, Shuo Li, Qiong Yang, Michelle Luciano, Sherif Karama, Lindsay Lewis, Mark E. Bastin, Mathew A. Harris, Joanna M. Wardlaw, Ian E. Deary, Markus Scholz, Markus Loeffler, A. Veronica Witte, Frauke Beyer, Arno Villringer, Nicola J. Armstrong, Karen A. Mather, David Ames, Jiyang Jiang, John B. Kwok, Peter R. Schofield, Anbupalam Thalamuthu, Julian N. Trollor, Margaret J. Wright, Henry Brodaty, Wei Wen, Perminder S. Sachdev, Natalie Terzikhan, Tavia E. Evans, Hieab H. H. H. Adams, M. Arfan Ikram, Stefan Frenzel, Sandra van der Auwera-Palitschka, Katharina Wittfeld, Robin Bülow, Hans Jörgen Grabe, Christophe Tzourio, Aniket Mishra, Sophie Maingault, Stephanie Debette, Nathan A. Gillespie, Carol E. Franz, William S. Kremen, Linda Ding, Neda Jahanshad, Nenad Sestan, Zdenka Pausova, Sudha Seshadri, Tomas Paus

Date Published: 1st Jun 2020

Publication Type: Journal article

Genome-wide analysis of carotid plaque burden suggests a role of IL5 in men.
Genetical Statistics and Systems Biology

Abstract (Expand)

BACKGROUND: Carotid artery plaque is an established marker of subclinical atherosclerosis with pronounced sex-dimorphism. Here, we aimed to identify genetic variants associated with carotid plaque … burden (CPB) and to examine potential sex-specific genetic effects on plaque sizes. METHODS AND RESULTS: We defined six operationalizations of CPB considering plaques in common carotid arteries, carotid bulb, and internal carotid arteries. We performed sex-specific genome-wide association analyses for all traits in the LIFE-Adult cohort (n = 727 men and n = 550 women) and tested significantly associated loci for sex-specific effects. In order to identify causal genes, we analyzed candidate gene expression data for correlation with CPB traits and corresponding sex-specific effects. Further, we tested if previously reported SNP associations with CAD and plaque prevalence are also associated with CBP. We found seven loci with suggestive significance for CPB (p<3.33x10-7), explaining together between 6 and 13% of the CPB variance. Sex-specific analysis showed a genome-wide significant hit for men at 5q31.1 (rs201629990, beta = -0.401, p = 5.22x10-9), which was not associated in women (beta = -0.127, p = 0.093) with a significant difference in effect size (p = 0.008). Analyses of gene expression data suggested IL5 as the most plausible candidate, as it reflected the same sex-specific association with CPBs (p = 0.037). Known plaque prevalence or CAD loci showed no enrichment in the association with CPB. CONCLUSIONS: We showed that CPB is a complementary trait in analyzing genetics of subclinical atherosclerosis. We detected a novel locus for plaque size in men only suggesting a role of IL5. Several estrogen response elements in this locus point towards a functional explanation of the observed sex-specific effect.

Authors: J. Pott, F. Beutner, K. Horn, H. Kirsten, K. Olischer, K. Wirkner, M. Loeffler, M. Scholz

Date Published: 30th May 2020

Publication Type: Journal article

Human Diseases: cardiovascular system disease, atherosclerosis

Mendelian randomization analysis does not support causal associations of birth weight with hypertension risk and blood pressure in adulthood.
Genetical Statistics and Systems Biology

Abstract (Expand)

Epidemiology studies suggested that low birthweight was associated with a higher risk of hypertension in later life. However, little is known about the causality of such associations. In our study, we … evaluated the causal association of low birthweight with adulthood hypertension following a standard analytic protocol using the study-level data of 183,433 participants from 60 studies (CHARGE-BIG consortium), as well as that with blood pressure using publicly available summary-level genome-wide association data from EGG consortium of 153,781 participants, ICBP consortium and UK Biobank cohort together of 757,601 participants. We used seven SNPs as the instrumental variable in the study-level analysis and 47 SNPs in the summary-level analysis. In the study-level analyses, decreased birthweight was associated with a higher risk of hypertension in adults (the odds ratio per 1 standard deviation (SD) lower birthweight, 1.22; 95% CI 1.16 to 1.28), while no association was found between genetically instrumented birthweight and hypertension risk (instrumental odds ratio for causal effect per 1 SD lower birthweight, 0.97; 95% CI 0.68 to 1.41). Such results were consistent with that from the summary-level analyses, where the genetically determined low birthweight was not associated with blood pressure measurements either. One SD lower genetically determined birthweight was not associated with systolic blood pressure (\textgreekb = - 0.76, 95% CI - 2.45 to 1.08 mmHg), 0.06 mmHg lower diastolic blood pressure (\textgreekb = - 0.06, 95% CI - 0.93 to 0.87 mmHg), or pulse pressure (\textgreekb = - 0.65, 95% CI - 1.38 to 0.69 mmHg, all p \textgreater 0.05). Our findings suggest that the inverse association of birthweight with hypertension risk from observational studies was not supported by large Mendelian randomization analyses.

Authors: Yan Zheng, Tao Huang, Tiange Wang, Zhendong Mei, Zhonghan Sun, Tao Zhang, Christina Ellervik, Jin-Fang Chai, Xueling Sim, Rob M. van Dam, E-Shyong Tai, Woon-Puay Koh, Rajkumar Dorajoo, Seang-Mei Saw, Charumathi Sabanayagam, Tien Yin Wong, Preeti Gupta, Peter Rossing, Tarunveer S. Ahluwalia, Rebecca K. Vinding, Hans Bisgaard, Klaus Bønnelykke, Yujie Wang, Mariaelisa Graff, Trudy Voortman, Frank J. A. van Rooij, Albert Hofman, Diana van Heemst, Raymond Noordam, Angela C. Estampador, Tibor V. Varga, Cornelia Enzenbach, Markus Scholz, Joachim Thiery, Ralph Burkhardt, Marju Orho-Melander, Christina-Alexandra Schulz, Ulrika Ericson, Emily Sonestedt, Michiaki Kubo, Masato Akiyama, Ang Zhou, Tuomas O. Kilpeläinen, Torben Hansen, Marcus E. Kleber, Graciela Delgado, Mark McCarthy, Rozenn N. Lemaitre, Janine F. Felix, Vincent W. V. Jaddoe, Ying Wu, Karen L. Mohlke, Terho Lehtimäki, Carol A. Wang, Craig E. Pennell, Heribert Schunkert, Thorsten Kessler, Lingyao Zeng, Christina Willenborg, Annette Peters, Wolfgang Lieb, Veit Grote, Peter Rzehak, Berthold Koletzko, Jeanette Erdmann, Matthias Munz, Tangchun Wu, Meian He, Caizheng Yu, Cécile Lecoeur, Philippe Froguel, Dolores Corella, Luis A. Moreno, Chao-Qiang Lai, Niina Pitkänen, Colin A. Boreham, Paul M. Ridker, Frits R. Rosendaal, Renée de Mutsert, Chris Power, Lavinia Paternoster, Thorkild I. A. Sørensen, Anne Tjønneland, Kim Overvad, Luc Djousse, Fernando Rivadeneira, Nanette R. Lee, Olli T. Raitakari, Mika Kähönen, Jorma Viikari, Jean-Paul Langhendries, Joaquin Escribano, Elvira Verduci, George Dedoussis, Inke König, Beverley Balkau, Oscar Coltell, Jean Dallongeville, Aline Meirhaeghe, Philippe Amouyel, Frédéric Gottrand, Katja Pahkala, Harri Niinikoski, Elina Hyppönen, Winfried März, David A. Mackey, Dariusz Gruszfeld, Katherine L. Tucker, Frédéric Fumeron, Ramon Estruch, Jose M. Ordovas, Donna K. Arnett, Dennis O. Mook-Kanamori, Dariush Mozaffarian, Bruce M. Psaty, Kari E. North, Daniel I. Chasman, Lu Qi

Date Published: 7th May 2020

Publication Type: Journal article

Adipocytokines are not associated with gestational diabetes mellitus but with pregnancy status.
Genetical Statistics and Systems Biology

Abstract (Expand)

AIMS Adipose tissue-secreted proteins, i.e. adipocytokines, have been identified as potential mediators linking fat mass and adipose tissue dysfunction with impaired glucose homeostasis, alterations …s in the inflammatory status, and risk of diabetes. The aim of this study was to determine whether seven circulating adipocytokines are associated with gestational diabetes mellitus (GDM) or are altered by metabolic and weight changes during pregnancy itself. METHODS A panel of seven adipocytokines (i.e. adiponectin, adipocyte fatty acid-binding protein, chemerin, leptin, Pro-Enkephalin, progranulin, and Pro-Neurotensin) was quantified in serum in a cross-sectional cohort of 222 women with the following three groups matched for age and body mass index: (i) 74 pregnant women with GDM; (ii) 74 pregnant women without GDM; and (iii) 74 non-pregnant and healthy women. A stepwise statistical approach was used by performing pairwise comparisons, principal component analysis (PCA), and partial least square discriminant analysis (PLS-DA). RESULTS Five out of seven adipocytokines were dysregulated between pregnant and non-pregnant women, i.e. adiponectin, chemerin, leptin, Pro-Enkephalin, and progranulin. None of the adipocytokines significantly differed between GDM and non-GDM status during pregnancy. The same five adipocytokines clustered in a principal component representing pregnancy-induced effects. Fasting insulin was the most relevant parameter in the discrimination of GDM as compared to pregnant women without GDM, whereas chemerin and adiponectin were most relevant factors to discriminate pregnancy status. CONCLUSIONS Pregnancy status but not presence of GDM can be distinguished by the seven investigated adipocytokines in discrimination analyses.

Authors: Thomas Ebert, Claudia Gebhardt, Markus Scholz, Dorit Schleinitz, Matthias Blüher, Michael Stumvoll, Peter Kovacs, Mathias Fasshauer, Anke Tönjes

Date Published: 10th Apr 2020

Publication Type: Journal article

Nonobstructive Coronary Artery Disease at Angiography and Gender-Specific Indicators for Cardiovascular Events: 5-Year Follow-Up of the LIFE Heart Study
Genetical Statistics and Systems Biology

Abstract (Expand)

Background: Patients with cardiac complaints but without confirmed diagnosis of coronary heart disease by angiography frequently develop cardiac events in the following years. This follow-up study … investigated the frequency of cardiac symptoms and cardiovascular events (CVE) 5 years after initial angiography of patients with nonobstructive coronary artery disease (NobCAD, LIFE Heart study), with the aim to identify gender-specific indicators for CVE. Methods: In 2014/2015, 1462 women and men with NobCAD, defined as no or non-relevant obstructive coronary artery disease were identified among 2660 subjects participating in the observational angiographic LIFE Heart study. Questionnaires of 820 responding patients were analyzed. Results: The median observation time was 55 months. Cardiac symptoms were found in 53.6% of all patients, significantly more often in women than in men (59.4% vs. 48.8%; p = 0.002). CVE occurred in 46.1% of all participants (n = 378/820). Patients with cardiac symptoms had a 2.94 time higher risk for CVE than those without cardiac symptoms (p \textless 0.001). Men with no cardiac symptoms had significantly more CVE (p = 0.042) than women. Common risk factors for CVE comprised cardiac symptoms, atrial fibrillation, and age. Sex-specific risk factors comprised body mass index (BMI) \geq25 kg/m2 for women and anxiety for men. Conclusions: Patients with cardiac symptoms have about three times higher risk for CVE within 5 years than patients without cardiac symptoms. Sex differences exist in patients without symptoms where men were at higher risk for CVE. Atrial fibrillation was the strongest indicator for CVE, whereas anxiety was an indicator only in men and BMI \geq25 kg/m2 only in women, suggesting sex- and gender-specific phenotypic profiles.

Authors: Ahmad T. Nauman, Andrej Teren, Samira Zeynalova, Joachim Thiery, Vera Regitz-Zagrosek, Markus Scholz, Ute Seeland

Date Published: 1st Mar 2020

Publication Type: Journal article

HLA Class II Allele Analyses Implicate Common Genetic Components in Type 1 and Non-Insulin-Treated Type 2 Diabetes
Genetical Statistics and Systems Biology

Abstract (Expand)

CONTEXT Common genetic susceptibility may underlie the frequently observed co-occurrence of type 1 and type 2 diabetes in families. Given the role of HLA class II genes in the pathophysiology of type …e 1 diabetes, the aim of the present study was to test the association of high density imputed human leukocyte antigen (HLA) genotypes with type 2 diabetes. OBJECTIVES AND DESIGN Three cohorts (Ntotal = 10 413) from Leipzig, Germany were included in this study: LIFE-Adult (N = 4649), LIFE-Heart (N = 4815) and the Sorbs (N = 949) cohort. Detailed metabolic phenotyping and genome-wide single nucleotide polymorphism (SNP) data were available for all subjects. Using 1000 Genome imputation data, HLA genotypes were imputed on 4-digit level and association tests for type 2 diabetes, and related metabolic traits were conducted. RESULTS In a meta-analysis including all 3 cohorts, the absence of HLA-DRB5 was associated with increased risk of type 2 diabetes (P = 0.001). In contrast, HLA-DQB*06:02 and HLA-DQA*01:02 had a protective effect on type 2 diabetes (P = 0.005 and 0.003, respectively). Both alleles are part of the well-established type 1 diabetes protective haplotype DRB1*15:01~DQA1*01:02~DQB1*06:02, which was also associated with reduced risk of type 2 diabetes (OR 0.84; P = 0.005). On the contrary, the DRB1*07:01~DQA1*02:01~DQB1*03:03 was identified as a risk haplotype in non-insulin-treated diabetes (OR 1.37; P = 0.002). CONCLUSIONS Genetic variation in the HLA class II locus exerts risk and protective effects on non-insulin-treated type 2 diabetes. Our data suggest that the genetic architecture of type 1 diabetes and type 2 diabetes might share common components on the HLA class II locus.

Authors: Thomas Jacobi, Lucas Massier, Nora Klöting, Katrin Horn, Alexander Schuch, Peter Ahnert, Christoph Engel, Markus Löffler, Ralph Burkhardt, Joachim Thiery, Anke Tönjes, Michael Stumvoll, Matthias Blüher, Ilias Doxiadis, Markus Scholz, Peter Kovacs

Date Published: 1st Mar 2020

Publication Type: Journal article

Sepsis-associated acute respiratory distress syndrome in individuals of European ancestry: a genome-wide association study
Genetical Statistics and Systems Biology

Abstract (Expand)

BACKGROUND Acute respiratory distress syndrome (ARDS) is a lung inflammatory process caused mainly by sepsis. Most previous studies that identified genetic risks for ARDS focused on candidates with …h biological relevance. We aimed to identify novel genetic variants associated with ARDS susceptibility and to provide complementary functional evidence of their effect in gene regulation. METHODS We did a case-control genome-wide association study (GWAS) of 1935 European individuals, using patients with sepsis-associated ARDS as cases and patients with sepsis without ARDS as controls. The discovery stage included 672 patients admitted into a network of Spanish intensive care units between January, 2002, and January, 2017. The replication stage comprised 1345 individuals from two independent datasets from the MESSI cohort study (Sep 22, 2008-Nov 30, 2017; USA) and the VISEP (April 1, 2003-June 30, 2005) and MAXSEP (Oct 1, 2007-March 31, 2010) trials of the SepNet study (Germany). Results from discovery and replication stages were meta-analysed to identify association signals. We then used RNA sequencing data from lung biopsies, in-silico analyses, and luciferase reporter assays to assess the functionallity of associated variants. FINDINGS We identified a novel genome-wide significant association with sepsis-associated ARDS susceptibility (rs9508032, odds ratio [OR] 0·61, 95% CI 0·41-0·91, p=5·18 \times 10-8) located within the Fms-related tyrosine kinase 1 (FLT1) gene, which encodes vascular endothelial growth factor receptor 1 (VEGFR-1). The region containing the sentinel variant and its best proxies acted as a silencer for the FLT1 promoter, and alleles with protective effects in ARDS further reduced promoter activity (p=0·0047). A literature mining of all previously described ARDS genes validated the association of vascular endothelial growth factor A (VEGFA; OR 0·55, 95% CI 0·41-0·73; p=4·69 \times 10-5). INTERPRETATION A common variant within the FLT1 gene is associated with sepsis-associated ARDS. Our findings support a role for the vascular endothelial growth factor signalling pathway in ARDS pathogenesis and identify VEGFR-1 as a potential therapeutic target. FUNDING Instituto de Salud Carlos III, European Regional Development Funds, Instituto Tecnológico y de Energías Renovables.

Authors: Beatriz Guillen-Guio, Jose M. Lorenzo-Salazar, Shwu-Fan Ma, Pei-Chi Hou, Tamara Hernandez-Beeftink, Almudena Corrales, M. Isabel García-Laorden, Jonathan Jou, Elena Espinosa, Arturo Muriel, David Domínguez, Leonardo Lorente, María M. Martín, Carlos Rodríguez-Gallego, Jordi Solé-Violán, Alfonso Ambrós, Demetrio Carriedo, Jesús Blanco, José M. Añón, John P. Reilly, Tiffanie K. Jones, Caroline Ag Ittner, Rui Feng, Franziska Schöneweck, Michael Kiehntopf, Imre Noth, Markus Scholz, Frank M. Brunkhorst, André Scherag, Nuala J. Meyer, Jesús Villar, Carlos Flores

Date Published: 1st Mar 2020

Publication Type: Journal article

Propionic Acid Shapes the Multiple Sclerosis Disease Course by an Immunomodulatory Mechanism
Genetical Statistics and Systems Biology

Abstract (Expand)

Short-chain fatty acids are processed from indigestible dietary fibers by gut bacteria and have immunomodulatory properties. Here, we investigate propionic acid (PA) in multiple sclerosis (MS), an … autoimmune and neurodegenerative disease. Serum and feces of subjects with MS exhibited significantly reduced PA amounts compared with controls, particularly after the first relapse. In a proof-of-concept study, we supplemented PA to therapy-naive MS patients and as an add-on to MS immunotherapy. After 2 weeks of PA intake, we observed a significant and sustained increase of functionally competent regulatory T (Treg) cells, whereas Th1 and Th17 cells decreased significantly. Post-hoc analyses revealed a reduced annual relapse rate, disability stabilization, and reduced brain atrophy after 3 years of PA intake. Functional microbiome analysis revealed increased expression of Treg-cell-inducing genes in the intestine after PA intake. Furthermore, PA normalized Treg cell mitochondrial function and morphology in MS. Our findings suggest that PA can serve as a potent immunomodulatory supplement to MS drugs.

Authors: Alexander Duscha, Barbara Gisevius, Sarah Hirschberg, Nissan Yissachar, Gabriele I. Stangl, Eva Eilers, Verian Bader, Stefanie Haase, Johannes Kaisler, Christina David, Ruth Schneider, Riccardo Troisi, Daniel Zent, Tobias Hegelmaier, Nikolaos Dokalis, Sara Gerstein, Sara Del Mare-Roumani, Sivan Amidror, Ori Staszewski, Gereon Poschmann, Kai Stühler, Frank Hirche, Andras Balogh, Stefan Kempa, Pascal Träger, Mario M. Zaiss, Jacob Bak Holm, Megan G. Massa, Henrik Bjørn Nielsen, Andreas Faissner, Carsten Lukas, Sören G. Gatermann, Markus Scholz, Horst Przuntek, Marco Prinz, Sofia K. Forslund, Konstanze F. Winklhofer, Dominik N. Müller, Ralf A. Linker, Ralf Gold, Aiden Haghikia

Date Published: 1st Mar 2020

Publication Type: Journal article

Markov State Modelling of Disease Courses and Mortality Risks of Patients with Community-Acquired Pneumonia
Genetical Statistics and Systems Biology

Abstract (Expand)

Community-acquired pneumonia (CAP) is one of the most frequent infectious diseases worldwide, with high lethality. Risk evaluation is well established at hospital admission, and re-evaluation is advised … for patients at higher risk. However, severe disease courses may develop from all levels of severity. We propose a stochastic continuous-time Markov model describing daily development of time courses of CAP severity. Disease states were defined based on the Sequential Organ Failure Assessment (SOFA) score. Model calibration was based on longitudinal data from 2838 patients with a primary diagnosis of CAP from four clinical studies (PROGRESS, MAXSEP, SISPCT, VISEP). We categorized CAP severity into five disease states and estimated transition probabilities for CAP progression between these states and corresponding sojourn times. Good agreement between model predictions and clinical data was observed. Time courses of mortality were correctly predicted for up to 28 days, including validation with patient data not used for model calibration. We conclude that CAP disease course follows a Markov process, suggesting the necessity of daily monitoring and re-evaluation of patient’s risk. Our model can be used for regular updates of risk assessments of patients and could improve the design of clinical trials by estimating transition rates for different risk groups.

Authors: Jens Przybilla, Peter Ahnert, Holger Bogatsch, Frank Bloos, Frank M. Brunkhorst, Critical Care Trials Group SepNet, Study Group Progress, Michael Bauer, Markus Loeffler, Martin Witzenrath, Norbert Suttorp, Markus Scholz

Date Published: 1st Feb 2020

Publication Type: Journal article

Neutralizing Complement C5a Protects Mice with Pneumococcal Pulmonary Sepsis
Genetical Statistics and Systems Biology

Abstract (Expand)

BACKGROUND Community-acquired pneumonia and associated sepsis cause high mortality despite antibiotic treatment. Uncontrolled inflammatory host responses contribute to the unfavorable outcome by driving …g lung and extrapulmonary organ failure. The complement fragment C5a holds significant proinflammatory functions and is associated with tissue damage in various inflammatory conditions. The authors hypothesized that C5a concentrations are increased in pneumonia and C5a neutralization promotes barrier stabilization in the lung and is protective in pneumococcal pulmonary sepsis. METHODS The authors investigated regulation of C5a in pneumonia in a prospective patient cohort and in experimental pneumonia. Two complementary models of murine pneumococcal pneumonia were applied. Female mice were treated with NOX-D19, a C5a-neutralizing L-RNA-aptamer. Lung, liver, and kidney injury and the inflammatory response were assessed by measuring pulmonary permeability (primary outcome), pulmonary and blood leukocytes, cytokine concentrations in lung and blood, and bacterial load in lung, spleen, and blood, and performing histologic analyses of tissue damage, apoptosis, and fibrin deposition (n = 5 to 13). RESULTS In hospitalized patients with pneumonia (n = 395), higher serum C5a concentrations were observed compared to healthy subjects (n = 24; 6.3 nmol/l [3.9 to 10.0] vs. 4.5 nmol/l [3.8 to 6.6], median [25 to 75% interquartile range]; difference: 1.4 [95% CI, 0.1 to 2.9]; P = 0.029). Neutralization of C5a in mice resulted in lower pulmonary permeability in pneumococcal pneumonia (1.38 \pm 0.89 vs. 3.29 \pm 2.34, mean \pm SD; difference: 1.90 [95% CI, 0.15 to 3.66]; P = 0.035; n = 10 or 11) or combined severe pneumonia and mechanical ventilation (2.56 \pm 1.17 vs. 7.31 \pm 5.22; difference: 4.76 [95% CI, 1.22 to 8.30]; P = 0.011; n = 9 or 10). Further, C5a neutralization led to lower blood granulocyte colony-stimulating factor concentrations and protected against sepsis-associated liver injury. CONCLUSIONS Systemic C5a is elevated in pneumonia patients. Neutralizing C5a protected against lung and liver injury in pneumococcal pneumonia in mice. Early neutralization of C5a might be a promising adjunctive treatment strategy to improve outcome in community-acquired pneumonia. : WHAT WE ALREADY KNOW ABOUT THIS TOPIC: Pneumonia, sepsis, and immune dysregulation cause morbidity and mortalityC5a is a component of the complement system and a proinflammatory mediator that modulates the innate immune response in critical illnessDisruption of the C5a receptor axis with antibodies or antagonists was previously protective in various animal sepsis models WHAT THIS ARTICLE TELLS US THAT IS NEW: In hospitalized patients with community-acquired pneumonia, serum C5a concentrations were 1.4-fold higher compared to healthy subjectsIn two mouse models of pneumonia and sepsis, NOX-D19, a C5a-neutralizing L-RNA aptamer, caused lower pulmonary hyperpermeability and sepsis-related acute liver injury.

Authors: Holger Müller-Redetzky, Ute Kellermann, Sandra-Maria Wienhold, Birgitt Gutbier, Jasmin Lienau, Katharina Hellwig, Katrin Reppe, Eleftheria Letsiou, Thomas Tschernig, Markus Scholz, Peter Ahnert, Christian Maasch, Kai Hoehlig, Sven Klussmann, Axel Vater, Theresa C. Firsching, Judith Hoppe, Norbert Suttorp, Martin Witzenrath

Date Published: 2020

Publication Type: Journal article

Genome-wide association meta-analyses and fine-mapping elucidate pathways influencing albuminuria
Genetical Statistics and Systems Biology

Abstract (Expand)

Increased levels of the urinary albumin-to-creatinine ratio (UACR) are associated with higher risk of kidney disease progression and cardiovascular events, but underlying mechanisms are incompletely … understood. Here, we conduct trans-ethnic (n = 564,257) and European-ancestry specific meta-analyses of genome-wide association studies of UACR, including ancestry- and diabetes-specific analyses, and identify 68 UACR-associated loci. Genetic correlation analyses and risk score associations in an independent electronic medical records database (n = 192,868) reveal connections with proteinuria, hyperlipidemia, gout, and hypertension. Fine-mapping and trans-Omics analyses with gene expression in 47 tissues and plasma protein levels implicate genes potentially operating through differential expression in kidney (including TGFB1, MUC1, PRKCI, and OAF), and allow coupling of UACR associations to altered plasma OAF concentrations. Knockdown of OAF and PRKCI orthologs in Drosophila nephrocytes reduces albumin endocytosis. Silencing fly PRKCI further impairs slit diaphragm formation. These results generate a priority list of genes and pathways for translational research to reduce albuminuria.

Authors: Alexander Teumer, Yong Li, Sahar Ghasemi, Bram P. Prins, Matthias Wuttke, Tobias Hermle, Ayush Giri, Karsten B. Sieber, Chengxiang Qiu, Holger Kirsten, Adrienne Tin, Audrey Y. Chu, Nisha Bansal, Mary F. Feitosa, Lihua Wang, Jin-Fang Chai, Massimiliano Cocca, Christian Fuchsberger, Mathias Gorski, Anselm Hoppmann, Katrin Horn, Man Li, Jonathan Marten, Damia Noce, Teresa Nutile, Sanaz Sedaghat, Gardar Sveinbjornsson, Bamidele O. Tayo, Peter J. van der Most, Yizhe Xu, Zhi Yu, Lea Gerstner, Johan Ärnlöv, Stephan J. L. Bakker, Daniela Baptista, Mary L. Biggs, Eric Boerwinkle, Hermann Brenner, Ralph Burkhardt, Robert J. Carroll, Miao-Li Chee, Miao-Ling Chee, Mengmeng Chen, Ching-Yu Cheng, James P. Cook, Josef Coresh, Tanguy Corre, John Danesh, Martin H. de Borst, Alessandro de Grandi, Renée de Mutsert, Aiko P. J. de Vries, Frauke Degenhardt, Katalin Dittrich, Jasmin Divers, Kai-Uwe Eckardt, Georg Ehret, Karlhans Endlich, Janine F. Felix, Oscar H. Franco, Andre Franke, Barry I. Freedman, Sandra Freitag-Wolf, Ron T. Gansevoort, Vilmantas Giedraitis, Martin Gögele, Franziska Grundner-Culemann, Daniel F. Gudbjartsson, Vilmundur Gudnason, Pavel Hamet, Tamara B. Harris, Andrew A. Hicks, Hilma Holm, Valencia Hui Xian Foo, Shih-Jen Hwang, M. Arfan Ikram, Erik Ingelsson, Vincent W. V. Jaddoe, Johanna Jakobsdottir, Navya Shilpa Josyula, Bettina Jung, Mika Kähönen, Chiea-Chuen Khor, Wieland Kiess, Wolfgang Koenig, Antje Körner, Peter Kovacs, Holly Kramer, Bernhard K. Krämer, Florian Kronenberg, Leslie A. Lange, Carl D. Langefeld, Jeannette Jen-Mai Lee, Terho Lehtimäki, Wolfgang Lieb, Su-Chi Lim, Lars Lind, Cecilia M. Lindgren, Jianjun Liu, Markus Loeffler, Leo-Pekka Lyytikäinen, Anubha Mahajan, Joseph C. Maranville, Deborah Mascalzoni, Barbara McMullen, Christa Meisinger, Thomas Meitinger, Kozeta Miliku, Dennis O. Mook-Kanamori, Martina Müller-Nurasyid, Josyf C. Mychaleckyj, Matthias Nauck, Kjell Nikus, Boting Ning, Raymond Noordam, Jeffrey O’ Connell, Isleifur Olafsson, Nicholette D. Palmer, Annette Peters, Anna I. Podgornaia, Belen Ponte, Tanja Poulain, Peter P. Pramstaller, Ton J. Rabelink, Laura M. Raffield, Dermot F. Reilly, Rainer Rettig, Myriam Rheinberger, Kenneth M. Rice, Fernando Rivadeneira, Heiko Runz, Kathleen A. Ryan, Charumathi Sabanayagam, Kai-Uwe Saum, Ben Schöttker, Christian M. Shaffer, Yuan Shi, Albert V. Smith, Konstantin Strauch, Michael Stumvoll, Benjamin B. Sun, Silke Szymczak, E-Shyong Tai, Nicholas Y. Q. Tan, Kent D. Taylor, Andrej Teren, Yih-Chung Tham, Joachim Thiery, Chris H. L. Thio, Hauke Thomsen, Unnur Thorsteinsdottir, Anke Tönjes, Johanne Tremblay, André G. Uitterlinden, Pim van der Harst, Niek Verweij, Suzanne Vogelezang, Uwe Völker, Melanie Waldenberger, Chaolong Wang, Otis D. Wilson, Charlene Wong, Tien-Yin Wong, Qiong Yang, Masayuki Yasuda, Shreeram Akilesh, Murielle Bochud, Carsten A. Böger, Olivier Devuyst, Todd L. Edwards, Kevin Ho, Andrew P. Morris, Afshin Parsa, Sarah A. Pendergrass, Bruce M. Psaty, Jerome I. Rotter, Kari Stefansson, James G. Wilson, Katalin Susztak, Harold Snieder, Iris M. Heid, Markus Scholz, Adam S. Butterworth, Adriana M. Hung, Cristian Pattaro, Anna Köttgen

Date Published: 1st Dec 2019

Publication Type: Journal article

Genetic architecture of subcortical brain structures in 38,851 individuals
Genetical Statistics and Systems Biology

Abstract (Expand)

Subcortical brain structures are integral to motion, consciousness, emotions and learning. We identified common genetic variation related to the volumes of the nucleus accumbens, amygdala, brainstem, … caudate nucleus, globus pallidus, putamen and thalamus, using genome-wide association analyses in almost 40,000 individuals from CHARGE, ENIGMA and UK Biobank. We show that variability in subcortical volumes is heritable, and identify 48 significantly associated loci (40 novel at the time of analysis). Annotation of these loci by utilizing gene expression, methylation and neuropathological data identified 199 genes putatively implicated in neurodevelopment, synaptic signaling, axonal transport, apoptosis, inflammation/infection and susceptibility to neurological disorders. This set of genes is significantly enriched for Drosophila orthologs associated with neurodevelopmental phenotypes, suggesting evolutionarily conserved mechanisms. Our findings uncover novel biology and potential drug targets underlying brain development and disease.

Authors: Claudia L. Satizabal, Hieab H. H. Adams, Derrek P. Hibar, Charles C. White, Maria J. Knol, Jason L. Stein, Markus Scholz, Muralidharan Sargurupremraj, Neda Jahanshad, Gennady V. Roshchupkin, Albert V. Smith, Joshua C. Bis, Xueqiu Jian, Michelle Luciano, Edith Hofer, Alexander Teumer, Sven J. van der Lee, Jingyun Yang, Lisa R. Yanek, Tom V. Lee, Shuo Li, Yanhui Hu, Jia Yu Koh, John D. Eicher, Sylvane Desrivières, Alejandro Arias-Vasquez, Ganesh Chauhan, Lavinia Athanasiu, Miguel E. Rentería, Sungeun Kim, David Hoehn, Nicola J. Armstrong, Qiang Chen, Avram J. Holmes, Anouk den Braber, Iwona Kloszewska, Micael Andersson, Thomas Espeseth, Oliver Grimm, Lucija Abramovic, Saud Alhusaini, Yuri Milaneschi, Martina Papmeyer, Tomas Axelsson, Stefan Ehrlich, Roberto Roiz-Santiañez, Bernd Kraemer, Asta K. Håberg, Hannah J. Jones, G. Bruce Pike, Dan J. Stein, Allison Stevens, Janita Bralten, Meike W. Vernooij, Tamara B. Harris, Irina Filippi, A. Veronica Witte, Tulio Guadalupe, Katharina Wittfeld, Thomas H. Mosley, James T. Becker, Nhat Trung Doan, Saskia P. Hagenaars, Yasaman Saba, Gabriel Cuellar-Partida, Najaf Amin, Saima Hilal, Kwangsik Nho, Nazanin Mirza-Schreiber, Konstantinos Arfanakis, Diane M. Becker, David Ames, Aaron L. Goldman, Phil H. Lee, Dorret I. Boomsma, Simon Lovestone, Sudheer Giddaluru, Stephanie Le Hellard, Manuel Mattheisen, Marc M. Bohlken, Dalia Kasperaviciute, Lianne Schmaal, Stephen M. Lawrie, Ingrid Agartz, Esther Walton, Diana Tordesillas-Gutierrez, Gareth E. Davies, Jean Shin, Jonathan C. Ipser, Louis N. Vinke, Martine Hoogman, Tianye Jia, Ralph Burkhardt, Marieke Klein, Fabrice Crivello, Deborah Janowitz, Owen Carmichael, Unn K. Haukvik, Benjamin S. Aribisala, Helena Schmidt, Lachlan T. Strike, Ching-Yu Cheng, Shannon L. Risacher, Benno Pütz, Debra A. Fleischman, Amelia A. Assareh, Venkata S. Mattay, Randy L. Buckner, Patrizia Mecocci, Anders M. Dale, Sven Cichon, Marco P. Boks, Mar Matarin, Brenda W. J. H. Penninx, Vince D. Calhoun, M. Mallar Chakravarty, Andre F. Marquand, Christine Macare, Shahrzad Kharabian Masouleh, Jaap Oosterlaan, Philippe Amouyel, Katrin Hegenscheid, Jerome I. Rotter, Andrew J. Schork, David C. M. Liewald, Greig I. de Zubicaray, Tien Yin Wong, Li Shen, Philipp G. Sämann, Henry Brodaty, Joshua L. Roffman, Eco J. C. de Geus, Magda Tsolaki, Susanne Erk, Kristel R. van Eijk, Gianpiero L. Cavalleri, Nic J. A. van der Wee, Andrew M. McIntosh, Randy L. Gollub, Kazima B. Bulayeva, Manon Bernard, Jennifer S. Richards, Jayandra J. Himali, Markus Loeffler, Nanda Rommelse, Wolfgang Hoffmann, Lars T. Westlye, Maria C. Valdés Hernández, Narelle K. Hansell, Theo G. M. van Erp, Christiane Wolf, John B. J. Kwok, Bruno Vellas, Andreas Heinz, Loes M. Olde Loohuis, Norman Delanty, Beng-Choon Ho, Christopher R. K. Ching, Elena Shumskaya, Baljeet Singh, Albert Hofman, Dennis van der Meer, Georg Homuth, Bruce M. Psaty, Mark E. Bastin, Grant W. Montgomery, Tatiana M. Foroud, Simone Reppermund, Jouke-Jan Hottenga, Andrew Simmons, Andreas Meyer-Lindenberg, Wiepke Cahn, Christopher D. Whelan, Marjolein M. J. van Donkelaar, Qiong Yang, Norbert Hosten, Robert C. Green, Anbupalam Thalamuthu, Sebastian Mohnke, Hilleke E. Hulshoff Pol, Honghuang Lin, Clifford R. Jack, Peter R. Schofield, Thomas W. Mühleisen, Pauline Maillard, Steven G. Potkin, Wei Wen, Evan Fletcher, Arthur W. Toga, Oliver Gruber, Matthew Huentelman, George Davey Smith, Lenore J. Launer, Lars Nyberg, Erik G. Jönsson, Benedicto Crespo-Facorro, Nastassja Koen, Douglas N. Greve, André G. Uitterlinden, Daniel R. Weinberger, Vidar M. Steen, Iryna O. Fedko, Nynke A. Groenewold, Wiro J. Niessen, Roberto Toro, Christophe Tzourio, William T. Longstreth, M. Kamran Ikram, Jordan W. Smoller, Marie-Jose van Tol, Jessika E. Sussmann, Tomas Paus, Hervé Lemaître, Matthias L. Schroeter, Bernard Mazoyer, Ole A. Andreassen, Florian Holsboer, Chantal Depondt, Dick J. Veltman, Jessica A. Turner, Zdenka Pausova, Gunter Schumann, Daan van Rooij, Srdjan Djurovic, Ian J. Deary, Katie L. McMahon, Bertram Müller-Myhsok, Rachel M. Brouwer, Hilkka Soininen, Massimo Pandolfo, Thomas H. Wassink, Joshua W. Cheung, Thomas Wolfers, Jean-Luc Martinot, Marcel P. Zwiers, Matthias Nauck, Ingrid Melle, Nicholas G. Martin, Ryota Kanai, Eric Westman, René S. Kahn, Sanjay M. Sisodiya, Tonya White, Arvin Saremi, Hans van Bokhoven, Han G. Brunner, Henry Völzke, Margaret J. Wright, Dennis van ’t Ent, Markus M. Nöthen, Roel A. Ophoff, Jan K. Buitelaar, Guillén Fernández, Perminder S. Sachdev, Marcella Rietschel, Neeltje E. M. van Haren, Simon E. Fisher, Alexa S. Beiser, Clyde Francks, Andrew J. Saykin, Karen A. Mather, Nina Romanczuk-Seiferth, Catharina A. Hartman, Anita L. DeStefano, Dirk J. Heslenfeld, Michael W. Weiner, Henrik Walter, Pieter J. Hoekstra, Paul A. Nyquist, Barbara Franke, David A. Bennett, Hans J. Grabe, Andrew D. Johnson, Christopher Chen, Cornelia M. van Duijn, Oscar L. Lopez, Myriam Fornage, Joanna M. Wardlaw, Reinhold Schmidt, Charles DeCarli, Philip L. de Jager, Arno Villringer, Stéphanie Debette, Vilmundur Gudnason, Sarah E. Medland, Joshua M. Shulman, Paul M. Thompson, Sudha Seshadri, M. Arfan Ikram

Date Published: 1st Nov 2019

Publication Type: Journal article

Human brain arousal in the resting state: a genome-wide association study
Genetical Statistics and Systems Biology

Abstract (Expand)

Arousal affects cognition, emotion, and behavior and has been implicated in the etiology of psychiatric disorders. Although environmental conditions substantially contribute to the level of arousal, … stable interindividual characteristics are well-established and a genetic basis has been suggested. Here we investigated the molecular genetics of brain arousal in the resting state by conducting a genome-wide association study (GWAS). We selected N = 1877 participants from the population-based LIFE-Adult cohort. Participants underwent a 20-min eyes-closed resting state EEG, which was analyzed using the computerized VIGALL 2.1 (Vigilance Algorithm Leipzig). At the SNP-level, GWAS analyses revealed no genome-wide significant locus (p \textless 5E-8), although seven loci were suggestive (p \textless 1E-6). The strongest hit was an expression quantitative trait locus (eQTL) of TMEM159 (lead-SNP: rs79472635, p = 5.49E-8). Importantly, at the gene-level, GWAS analyses revealed significant evidence for TMEM159 (p = 0.013, Bonferroni-corrected). By mapping our SNPs to the GWAS results from the Psychiatric Genomics Consortium, we found that all corresponding markers of TMEM159 showed nominally significant associations with Major Depressive Disorder (MDD; 0.006 ≤ p ≤ 0.011). More specifically, variants associated with high arousal levels have previously been linked to an increased risk for MDD. In line with this, the MetaXcan database suggests increased expression levels of TMEM159 in MDD, as well as Autism Spectrum Disorder, and Alzheimer’s Disease. Furthermore, our pathway analyses provided evidence for a role of sodium/calcium exchangers in resting state arousal. In conclusion, the present GWAS identifies TMEM159 as a novel candidate gene which may modulate the risk for psychiatric disorders through arousal mechanisms. Our results also encourage the elaboration of the previously reported interrelations between ion-channel modulators, sleep-wake behavior, and psychiatric disorders.   Arousal affects cognition, emotion, and behavior and has been implicated in the etiology of psychiatric disorders. Although environmental conditions substantially contribute to the level of arousal, stable interindividual characteristics are well-established and a genetic basis has been suggested. Here we investigated the molecular genetics of brain arousal in the resting state by conducting a genome-wide association study (GWAS). We selected N = 1877 participants from the population-based LIFE-Adult cohort. Participants underwent a 20-min eyes-closed resting state EEG, which was analyzed using the computerized VIGALL 2.1 (Vigilance Algorithm Leipzig). At the SNP-level, GWAS analyses revealed no genome-wide significant locus (p \textless 5E-8), although seven loci were suggestive (p \textless 1E-6). The strongest hit was an expression quantitative trait locus (eQTL) of TMEM159 (lead-SNP: rs79472635, p = 5.49E-8). Importantly, at the gene-level, GWAS analyses revealed significant evidence for TMEM159 (p = 0.013, Bonferroni-corrected). By mapping our SNPs to the GWAS results from the Psychiatric Genomics Consortium, we found that all corresponding markers of TMEM159 showed nominally significant associations with Major Depressive Disorder (MDD; 0.006 ≤ p ≤ 0.011). More specifically, variants associated with high arousal levels have previously been linked to an increased risk for MDD. In line with this, the MetaXcan database suggests increased expression levels of TMEM159 in MDD, as well as Autism Spectrum Disorder, and Alzheimer’s Disease. Furthermore, our pathway analyses provided evidence for a role of sodium/calcium exchangers in resting state arousal. In conclusion, the present GWAS identifies TMEM159 as a novel candidate gene which may modulate the risk for psychiatric disorders through arousal mechanisms. Our results also encourage the elaboration of the previously reported interrelations between ion-channel modulators, sleep-wake behavior, and psychiatric disorders. // Arousal affects cognition, emotion, and behavior and has been implicated in the etiology of psychiatric disorders. Although environmental conditions substantially contribute to the level of arousal, stable interindividual characteristics are well-established and a genetic basis has been suggested. Here we investigated the molecular genetics of brain arousal in the resting state by conducting a genome-wide association study (GWAS). We selected N = 1877 participants from the population-based LIFE-Adult cohort. Participants underwent a 20-min eyes-closed resting state EEG, which was analyzed using the computerized VIGALL 2.1 (Vigilance Algorithm Leipzig). At the SNP-level, GWAS analyses revealed no genome-wide significant locus (p \textless 5E-8), although seven loci were suggestive (p \textless 1E-6). The strongest hit was an expression quantitative trait locus (eQTL) of TMEM159 (lead-SNP: rs79472635, p = 5.49E-8). Importantly, at the gene-level, GWAS analyses revealed significant evidence for TMEM159 (p = 0.013, Bonferroni-corrected). By mapping our SNPs to the GWAS results from the Psychiatric Genomics Consortium, we found that all corresponding markers of TMEM159 showed nominally significant associations with Major Depressive Disorder (MDD; 0.006 ≤ p ≤ 0.011). More specifically, variants associated with high arousal levels have previously been linked to an increased risk for MDD. In line with this, the MetaXcan database suggests increased expression levels of TMEM159 in MDD, as well as Autism Spectrum Disorder, and Alzheimer’s Disease. Furthermore, our pathway analyses provided evidence for a role of sodium/calcium exchangers in resting state arousal. In conclusion, the present GWAS identifies TMEM159 as a novel candidate gene which may modulate the risk for psychiatric disorders through arousal mechanisms. Our results also encourage the elaboration of the previously reported interrelations between ion-channel modulators, sleep-wake behavior, and psychiatric disorders.

Authors: Philippe Jawinski, Holger Kirsten, Christian Sander, Janek Spada, Christine Ulke, Jue Huang, Ralph Burkhardt, Markus Scholz, Tilman Hensch, Ulrich Hegerl

Date Published: 1st Nov 2019

Publication Type: Journal article

Circulating oxytocin is genetically determined and associated with obesity and impaired glucose tolerance
Genetical Statistics and Systems Biology

Abstract (Expand)

CONTEXT Despite the emerging evidence on the role of oxytocin (OXT) in metabolic diseases, there is a lack of well powered studies addressing the relationship of circulating OXT with obesity and diabetes. …. OBJECTIVES AND DESIGN Here, we measured OXT in a study cohort (n=721; 396 women, 325 men; mean age\pmSD - 47.7\pm15.2 years) with sub-phenotypes related to obesity including anthropometric traits such as body mass index (BMI; mean\pmSD - 47.7\pm15.2 kg/m2), waist-to-hip-ratio (WHR; 0.88\pm0.09), blood parameters (glucose - 5.32\pm0.50 mmol/l, insulin - 5.3\pm3.3 µU/ml, lipids) and oral glucose tolerance test (OGTT) to clarify the association with OXT. We also tested in a genome-wide association study (GWAS) whether the inter-individual variation in OXT serum levels might be explained by genetic variation. RESULTS The OXT concentration was increased in subjects with elevated BMI and positively correlated with WHR, waist circumference and triglyceride levels. The OXT concentration in subjects with BMI\textless25 kg/m2 was significantly lower (n=256; 78.6 pg/ml) than in subjects with a BMI between 25-30 kg/m2 (n=314; 98.5 pg/ml, p=6x10-6) and with BMI\textgreater30 kg/m2 (n=137; 106.4 pg/ml, p=8x10-6). OXT levels were also positively correlated with plasma glucose and insulin and were elevated in subjects with impaired glucose tolerance (p=4.6x10-3). Heritability of OXT was estimated to 12.8%. In a GWAS, two hits in linkage disequilibrium close (19kb) to the OXT reached genome-wide significant association (top-hit rs12625893, p=3.1x10-8, explained variance 3%). CONCLUSIONS Our data show that OXT is genetically affected by a variant in OXT and is associated with obesity and impaired glucose tolerance.

Authors: Mark Florian Joachim Weingarten, Markus Scholz, Tobias Wohland, Katrin Horn, Michael Stumvoll, Peter Kovacs, Anke Tönjes

Date Published: 1st Nov 2019

Publication Type: Journal article

Common variants in glyoxalase I do not increase chronic pancreatitis risk
Genetical Statistics and Systems Biology

Abstract (Expand)

INTRODUCTION Chronic pancreatitis (CP) may be caused by oxidative stress. An important source of reactive oxygen species (ROS) is the methylglyoxal-derived formation of advanced glycation endproducts …s (AGE). Methylglyoxal is detoxified by Glyoxalase I (GLO1). A reduction in GLO1 activity results in increased ROS. Single nucleotide polymorphisms (SNPs) of GLO1 have been linked to various inflammatory diseases. Here, we analyzed whether common GLO1 variants are associated with alcoholic (ACP) and non-alcoholic CP (NACP). METHODS Using melting curve analysis, we genotyped a screening cohort of 223 ACP, 218 NACP patients, and 328 controls for 11 tagging SNPs defined by the SNPinfo LD TAG SNP Selection tool and the functionally relevant variant rs4746. For selected variants the cohorts were extended to up to 1,441 patient samples. RESULTS In the ACP cohort, comparison of genotypes for rs1937780 between patients and controls displayed an ambiguous result in the screening cohort (p = 0.08). However, in the extended cohort of 1,441 patients no statistically significant association was found for the comparison of genotypes (p = 0.11), nor in logistic regression analysis (p = 0.214, OR 1.072, 95% CI 0.961-1.196). In the NACP screening cohort SNPs rs937662, rs1699012, and rs4746 displayed an ambiguous result when patients were compared to controls in the recessive or dominant model (p = 0.08, 0.08, and 0.07, respectively). Again, these associations were not confirmed in the extended cohorts (rs937662, dominant model: p = 0.07, logistic regression: p = 0.07, OR 1.207, 95% CI 0.985-1.480) or in the replication cohorts for rs4746 (Germany, p = 0.42, OR 1.080, 95% CI 0.673-1.124; France, p = 0.19, OR 0.90, 95% CI 0.76-1.06; China, p = 0.24, OR 1.18, 95% CI 0.90-1.54) and rs1699012 (Germany, Munich; p = 0.279, OR 0.903, 95% CI 0.750-1.087). CONCLUSIONS Common GLO1 variants do not increase chronic pancreatitis risk.

Authors: Tom Kaune, Marcus Hollenbach, Bettina Keil, Jian-Min Chen, Emmanuelle Masson, Carla Becker, Marko Damm, Claudia Ruffert, Robert Grützmann, Albrecht Hoffmeister, Rene H. M. Te Morsche, Giulia Martina Cavestro, Raffaella Alessia Zuppardo, Adrian Saftoiu, Ewa Malecka-Panas, Stanislaw Głuszek, Peter Bugert, Markus M. Lerch, Frank Ulrich Weiss, Wen-Bin Zou, Zhuan Liao, Peter Hegyi, Joost Ph Drenth, Jan Riedel, Claude Férec, Markus Scholz, Holger Kirsten, Andrea Tóth, Maren Ewers, Heiko Witt, Heidi Griesmann, Patrick Michl, Jonas Rosendahl

Date Published: 29th Oct 2019

Publication Type: Journal article

Target genes, variants, tissues and transcriptional pathways influencing human serum urate levels
Genetical Statistics and Systems Biology

Abstract (Expand)

Elevated serum urate levels cause gout and correlate with cardiometabolic diseases via poorly understood mechanisms. We performed a trans-ancestry genome-wide association study of serum urate in 457,690 … individuals, identifying 183 loci (147 previously unknown) that improve the prediction of gout in an independent cohort of 334,880 individuals. Serum urate showed significant genetic correlations with many cardiometabolic traits, with genetic causality analyses supporting a substantial role for pleiotropy. Enrichment analysis, fine-mapping of urate-associated loci and colocalization with gene expression in 47 tissues implicated the kidney and liver as the main target organs and prioritized potentially causal genes and variants, including the transcriptional master regulators in the liver and kidney, HNF1A and HNF4A. Experimental validation showed that HNF4A transactivated the promoter of ABCG2, encoding a major urate transporter, in kidney cells, and that HNF4A p.Thr139Ile is a functional variant. Transcriptional coregulation within and across organs may be a general mechanism underlying the observed pleiotropy between urate and cardiometabolic traits.

Authors: Adrienne Tin, Jonathan Marten, Victoria L. Halperin Kuhns, Yong Li, Matthias Wuttke, Holger Kirsten, Karsten B. Sieber, Chengxiang Qiu, Mathias Gorski, Zhi Yu, Ayush Giri, Gardar Sveinbjornsson, Man Li, Audrey Y. Chu, Anselm Hoppmann, Luke J. O’Connor, Bram Prins, Teresa Nutile, Damia Noce, Masato Akiyama, Massimiliano Cocca, Sahar Ghasemi, Peter J. van der Most, Katrin Horn, Yizhe Xu, Christian Fuchsberger, Sanaz Sedaghat, Saima Afaq, Najaf Amin, Johan Ärnlöv, Stephan J. L. Bakker, Nisha Bansal, Daniela Baptista, Sven Bergmann, Mary L. Biggs, Ginevra Biino, Eric Boerwinkle, Erwin P. Bottinger, Thibaud S. Boutin, Marco Brumat, Ralph Burkhardt, Eric Campana, Archie Campbell, Harry Campbell, Robert J. Carroll, Eulalia Catamo, John C. Chambers, Marina Ciullo, Maria Pina Concas, Josef Coresh, Tanguy Corre, Daniele Cusi, Sala Cinzia Felicita, Martin H. de Borst, Alessandro de Grandi, Renée de Mutsert, Aiko P. J. de Vries, Graciela Delgado, Ayşe Demirkan, Olivier Devuyst, Katalin Dittrich, Kai-Uwe Eckardt, Georg Ehret, Karlhans Endlich, Michele K. Evans, Ron T. Gansevoort, Paolo Gasparini, Vilmantas Giedraitis, Christian Gieger, Giorgia Girotto, Martin Gögele, Scott D. Gordon, Daniel F. Gudbjartsson, Vilmundur Gudnason, Toomas Haller, Pavel Hamet, Tamara B. Harris, Caroline Hayward, Andrew A. Hicks, Edith Hofer, Hilma Holm, Wei Huang, Nina Hutri-Kähönen, Shih-Jen Hwang, M. Arfan Ikram, Raychel M. Lewis, Erik Ingelsson, Johanna Jakobsdottir, Ingileif Jonsdottir, Helgi Jonsson, Peter K. Joshi, Navya Shilpa Josyula, Bettina Jung, Mika Kähönen, Yoichiro Kamatani, Masahiro Kanai, Shona M. Kerr, Wieland Kiess, Marcus E. Kleber, Wolfgang Koenig, Jaspal S. Kooner, Antje Körner, Peter Kovacs, Bernhard K. Krämer, Florian Kronenberg, Michiaki Kubo, Brigitte Kühnel, Martina La Bianca, Leslie A. Lange, Benjamin Lehne, Terho Lehtimäki, Jun Liu, Markus Loeffler, Ruth J. F. Loos, Leo-Pekka Lyytikäinen, Reedik Magi, Anubha Mahajan, Nicholas G. Martin, Winfried März, Deborah Mascalzoni, Koichi Matsuda, Christa Meisinger, Thomas Meitinger, Andres Metspalu, Yuri Milaneschi, Christopher J. O’Donnell, Otis D. Wilson, J. Michael Gaziano, Pashupati P. Mishra, Karen L. Mohlke, Nina Mononen, Grant W. Montgomery, Dennis O. Mook-Kanamori, Martina Müller-Nurasyid, Girish N. Nadkarni, Mike A. Nalls, Matthias Nauck, Kjell Nikus, Boting Ning, Ilja M. Nolte, Raymond Noordam, Jeffrey R. O’Connell, Isleifur Olafsson, Sandosh Padmanabhan, Brenda W. J. H. Penninx, Thomas Perls, Annette Peters, Mario Pirastu, Nicola Pirastu, Giorgio Pistis, Ozren Polasek, Belen Ponte, David J. Porteous, Tanja Poulain, Michael H. Preuss, Ton J. Rabelink, Laura M. Raffield, Olli T. Raitakari, Rainer Rettig, Myriam Rheinberger, Kenneth M. Rice, Federica Rizzi, Antonietta Robino, Igor Rudan, Alena Krajcoviechova, Renata Cifkova, Rico Rueedi, Daniela Ruggiero, Kathleen A. Ryan, Yasaman Saba, Erika Salvi, Helena Schmidt, Reinhold Schmidt, Christian M. Shaffer, Albert V. Smith, Blair H. Smith, Cassandra N. Spracklen, Konstantin Strauch, Michael Stumvoll, Patrick Sulem, Salman M. Tajuddin, Andrej Teren, Joachim Thiery, Chris H. L. Thio, Unnur Thorsteinsdottir, Daniela Toniolo, Anke Tönjes, Johanne Tremblay, André G. Uitterlinden, Simona Vaccargiu, Pim van der Harst, Cornelia M. van Duijn, Niek Verweij, Uwe Völker, Peter Vollenweider, Gerard Waeber, Melanie Waldenberger, John B. Whitfield, Sarah H. Wild, James F. Wilson, Qiong Yang, Weihua Zhang, Alan B. Zonderman, Murielle Bochud, James G. Wilson, Sarah A. Pendergrass, Kevin Ho, Afshin Parsa, Peter P. Pramstaller, Bruce M. Psaty, Carsten A. Böger, Harold Snieder, Adam S. Butterworth, Yukinori Okada, Todd L. Edwards, Kari Stefansson, Katalin Susztak, Markus Scholz, Iris M. Heid, Adriana M. Hung, Alexander Teumer, Cristian Pattaro, Owen M. Woodward, Veronique Vitart, Anna Köttgen

Date Published: 1st Oct 2019

Publication Type: Journal article

Der Leipzig Health Atlas
LHA - Leipzig Health Atlas

Abstract (Expand)

Die Notwendigkeit des Managements von Forschungsdaten ist von der Forschungscommunity erkannt – Sponsoren, Gesetzgeber, Verlage erwarten und fördern die Einhaltung der guten wissenschaftlichen Praxis, … was nicht nur die Archivierung umfasst, sondern auch die Verfügbarkeit von Forschungsdaten- und ergebnissen im Sinne der FAIR-Prinzipien. Der Leipzig Health Atlas (LHA) ist ein Projekt zur Präsentation und zum Austausch eines breiten Spektrums von Publikationen, (bio) medizinischen Daten (z.B. klinisch, epidemiologisch, molekular), Modellen und Tools z.B. zur Risikoberechnung in der Gesundheitsforschung. Die Verbundpartner decken hierbei einen breiten Bereich wissenschaftlicher Disziplinen ab, beginnend von medizinischer Systembiologie über klinische und epidemiologische Forschung bis zu ontologischer und dynamischer Modellierung. Derzeit sind 18 Forschungskonsortien beteiligt (u.a. zu den Domänen Lymphome, Gliome, Sepsis, Erblicher Darm- und Brustkrebs), die Daten aus klinischen Studien, Patientenkohorten, epidemiologischen Kohorten, teilweise mit umfangreichen molekularen und genetischen Profilen, sammeln. Die Modellierung umfasst algorithmische Phänotypklassifizierung, Risikovorhersage und Krankheitsdynamik. Wir konnten in einer ersten Entwicklungsphase zeigen, dass unsere webbasierte Plattform geeignet ist, um (1) Methoden zur Verfügung zu stellen, um individuelle Patientendaten aus Publikationen für eine Weiternutzung zugänglich zu machen, (2) algorithmische Werkzeuge zur Phänotypisierung und Risikoprofilerstellung zu präsentieren, (3) Werkzeuge zur Durchführung dynamischer Krankheits- und Therapiemodelle interaktiv verfügbar zu machen und (4) strukturierte Metadaten zu quantitativen und qualitativen Merkmalen bereit zu stellen. Die semantische Datenintegration liefert hierzu die Technologien (Ontologien und Datamining Werkzeuge) für die (semantische) Datenintegration und Wissensanreicherung. Darüber hinaus stellt sie Werkzeuge zur Verknüpfung eigener Daten, Analyseergebnisse, öffentlich zugänglicher Daten- und Metadaten-Repositorien sowie zur Verdichtung komplexer Daten zur Verfügung. Eine Arbeitsgruppe zur Applikationsentwicklung und –validierung entwickelt innovative paradigmatische Anwendungen für (1) die klinische Entscheidungsfindung für Krebsstudien, die genetische Beratung, für Risikovorhersagemodelle sowie Gewebe- und Krankheitsmodelle und (2) Anwendungen (sog. Apps), die sich auf die Charakterisierung neuer Phänotypen (z.B. ‚omics‘-Merkmale, Körpertypen, Referenzwerte) aus epidemiologischen Studien konzentrieren. Diese Anwendungen werden gemeinsam mit klinischen Experten, Genetikern, Systembiologen, Biometrikern und Bioinformatikern spezifiziert. Der LHA stellt Integrationstechnologie bereit und implementiert die Anwendungen für die User Communities unter Verwendung verschiedener Präsentationswerkzeuge bzw. Technologien (z.B. R-Shiny, i2b2, Kubernetes, SEEK). Dazu ist es erforderlich, die Daten und Metadaten vor dem Hochladen zu kuratieren, Erlaubnisse der Datenbesitzer einzuholen, die erforderlichen Datenschutzkriterien zu berücksichtigen und semantische Annotationen zu überprüfen. Zudem werden die zugelieferten Modellalgorithmen in einer qualitätsgesicherten Weise aufbereitet und, soweit anwendbar, online interaktiv zur Verfügung gestellt. Der LHA richtet sich insbesondere an die Zielgruppen Kliniker, Epidemiologen, Molekulargenetiker, Humangenetiker, Pathologen, Biostatistiker und Modellierer ist aber unter www.healthatlas.de öffentlich zugänglich – aus rechtlichen Gründen erfordert der Zugriff auf bestimmte Applikationen und Datensätze zusätzliche Autorisierung. Das Projekt wird über das BMBF Programm i:DSem (Integrative Datensemantik für die Systemmedizin, Förderkennzeichen 031L0026) gefördert.

Authors: F. A. Meineke, Sebastian Stäubert, Matthias Löbe, C. Beger, René Hänsel, A. Uciteli, H. Binder, T. Kirsten, M. Scholz, H. Herre, C. Engel, Markus Löffler

Date Published: 19th Sep 2019

Publication Type: Misc

Association of Birth Weight With Type 2 Diabetes and Glycemic Traits: A Mendelian Randomization Study
Genetical Statistics and Systems Biology

Abstract (Expand)

Importance Observational studies have shown associations of birth weight with type 2 diabetes (T2D) and glycemic traits, but it remains unclear whether these associations represent causal associations. …. Objective To test the association of birth weight with T2D and glycemic traits using a mendelian randomization analysis. Design, Setting, and Participants This mendelian randomization study used a genetic risk score for birth weight that was constructed with 7 genome-wide significant single-nucleotide polymorphisms. The associations of this score with birth weight and T2D were tested in a mendelian randomization analysis using study-level data. The association of birth weight with T2D was tested using both study-level data (7 single-nucleotide polymorphisms were used as an instrumental variable) and summary-level data from the consortia (43 single-nucleotide polymorphisms were used as an instrumental variable). Data from 180 056 participants from 49 studies were included. Main Outcomes and Measures Type 2 diabetes and glycemic traits. Results This mendelian randomization analysis included 49 studies with 41 155 patients with T2D and 80 008 control participants from study-level data and 34 840 patients with T2D and 114 981 control participants from summary-level data. Study-level data showed that a 1-SD decrease in birth weight due to the genetic risk score was associated with higher risk of T2D among all participants (odds ratio [OR], 2.10; 95% CI, 1.69-2.61; P = 4.03 \times 10-5), among European participants (OR, 1.96; 95% CI, 1.42-2.71; P = .04), and among East Asian participants (OR, 1.39; 95% CI, 1.18-1.62; P = .04). Similar results were observed from summary-level analyses. In addition, each 1-SD lower birth weight was associated with 0.189 SD higher fasting glucose concentration (\textgreekb = 0.189; SE = 0.060; P = .002), but not with fasting insulin, 2-hour glucose, or hemoglobin A1c concentration. Conclusions and Relevance In this study, a genetic predisposition to lower birth weight was associated with increased risk of T2D and higher fasting glucose concentration, suggesting genetic effects on retarded fetal growth and increased diabetes risk that either are independent of each other or operate through alterations of integrated biological mechanisms.

Authors: Tao Huang, Tiange Wang, Yan Zheng, Christina Ellervik, Xiang Li, Meng Gao, Zhe Fang, Jin-Fang Chai, Tarun Veer S. Ahluwalia, Yujie Wang, Trudy Voortman, Raymond Noordam, Alexis Frazier-Wood, Markus Scholz, Emily Sonestedt, Masato Akiyama, Rajkumar Dorajoo, Ang Zhou, Tuomas O. Kilpeläinen, Marcus E. Kleber, Sarah R. Crozier, Keith M. Godfrey, Rozenn Lemaitre, Janine F. Felix, Yuan Shi, Preeti Gupta, Chiea-Chuen Khor, Terho Lehtimäki, Carol A. Wang, Carla M. T. Tiesler, Elisabeth Thiering, Marie Standl, Peter Rzehak, Eirini Marouli, Meian He, Cécile Lecoeur, Dolores Corella, Chao-Qiang Lai, Luis A. Moreno, Niina Pitkänen, Colin A. Boreham, Tao Zhang, Seang Mei Saw, Paul M. Ridker, Mariaelisa Graff, Frank J. A. van Rooij, Andre G. Uitterlinden, Albert Hofman, Diana van Heemst, Frits R. Rosendaal, Renée de Mutsert, Ralph Burkhardt, Christina-Alexandra Schulz, Ulrika Ericson, Yoichiro Kamatani, Jian-Min Yuan, Chris Power, Torben Hansen, Thorkild I. A. Sørensen, Anne Tjønneland, Kim Overvad, Graciela Delgado, Cyrus Cooper, Luc Djousse, Fernando Rivadeneira, Karen Jameson, Wanting Zhao, Jianjun Liu, Nanette R. Lee, Olli Raitakari, Mika Kähönen, Jorma Viikari, Veit Grote, Jean-Paul Langhendries, Berthold Koletzko, Joaquin Escribano, Elvira Verduci, George Dedoussis, Caizheng Yu, Yih Chung Tham, Blanche Lim, Sing Hui Lim, Philippe Froguel, Beverley Balkau, Nadia R. Fink, Rebecca K. Vinding, Astrid Sevelsted, Hans Bisgaard, Oscar Coltell, Jean Dallongeville, Frédéric Gottrand, Katja Pahkala, Harri Niinikoski, Elina Hyppönen, Oluf Pedersen, Winfried März, Hazel Inskip, Vincent W. V. Jaddoe, Elaine Dennison, Tien Yin Wong, Charumathi Sabanayagam, E-Shyong Tai, Karen L. Mohlke, David A. Mackey, Dariusz Gruszfeld, Panagiotis Deloukas, Katherine L. Tucker, Frédéric Fumeron, Klaus Bønnelykke, Peter Rossing, Ramon Estruch, Jose M. Ordovas, Donna K. Arnett, Aline Meirhaeghe, Philippe Amouyel, Ching-Yu Cheng, Xueling Sim, Yik Ying Teo, Rob M. van Dam, Woon-Puay Koh, Marju Orho-Melander, Markus Loeffler, Michiaki Kubo, Joachim Thiery, Dennis O. Mook-Kanamori, Dariush Mozaffarian, Bruce M. Psaty, Oscar H. Franco, Tangchun Wu, Kari E. North, George Davey Smith, Jorge E. Chavarro, Daniel I. Chasman, Lu Qi

Date Published: 4th Sep 2019

Publication Type: Journal article

Clinical and lifestyle related factors influencing whole blood metabolite levels -- A comparative analysis of three large cohorts
Genetical Statistics and Systems Biology

Abstract (Expand)

Objective Human blood metabolites are influenced by a number of lifestyle and environmental factors. Identification of these factors and the proper quantification of their relevance provides insights …s into human biological and metabolic disease processes, is key for standardized translation of metabolite biomarkers into clinical applications, and is a prerequisite for comparability of data between studies. However, so far only limited data exist from large and well-phenotyped human cohorts and current methods for analysis do not fully account for the characteristics of these data. The primary aim of this study was to identify, quantify and compare the impact of a comprehensive set of clinical and lifestyle related factors on metabolite levels in three large human cohorts. To achieve this goal, we improve current methodology by developing a principled analysis approach, which could be translated to other cohorts and metabolite panels. Methods 63 Metabolites (amino acids, acylcarnitines) were quantified by liquid chromatography tandem mass spectrometry in three cohorts (total N~=~16,222). Supported by a simulation study evaluating various analytical approaches, we developed an analysis pipeline including preprocessing, identification, and quantification of factors affecting metabolite levels. We comprehensively identified uni- and multivariable metabolite associations considering 29 environmental and clinical factors and performed metabolic pathway enrichment and network analyses. Results Inverse normal transformation of batch corrected and outlier removed metabolite levels accompanied by linear regression analysis proved to be the best suited method to deal with the metabolite data. Association analyses revealed numerous uni- and multivariable significant associations. 15 of the analyzed 29 factors explained {\textgreater}1{\%} of variance for at least one of the metabolites. Strongest factors are application of steroid hormones, reticulocytes, waist-to-hip ratio, sex, haematocrit, and age. Effect sizes of factors are comparable across studies. Conclusions We introduced a principled approach for the analysis of MS data allowing identification, and quantification of effects of clinical and lifestyle factors with metabolite levels. We detected a number of known and novel associations broadening our understanding of the regulation of the human metabolome. The large heterogeneity observed between cohorts could almost completely be explained by differences in the distribution of influencing factors emphasizing the necessity of a proper confounder analysis when interpreting metabolite associations.

Authors: Carl Beuchel, Susen Becker, Julia Dittrich, Holger Kirsten, Anke Toenjes, Michael Stumvoll, Markus Loeffler, Holger Thiele, Frank Beutner, Joachim Thiery, Uta Ceglarek, Markus Scholz

Date Published: 17th Aug 2019

Publication Type: Not specified

Genetic association study of eight steroid hormones and implications for sexual dimorphism of coronary artery disease
LIFE Adult, Genetical Statistics and Systems Biology, LIFE Heart

Abstract (Expand)

CONTEXT: Steroid hormones are important regulators of physiological processes in humans and are under genetic control. A link to coronary artery disease (CAD) is supposed. OBJECTIVE: Our main objective …e was to identify genetic loci influencing steroid hormone levels. As secondary aim, we searched for causal effects of steroid hormones on CAD. DESIGN: We conducted genome-wide meta-association studies for eight steroid hormones: cortisol, DHEA-S, estradiol and testosterone in two independent cohorts (LIFE-Adult, LIFE-Heart, max. n=7667), and progesterone, 17-hydroxyprogesterone, androstenedione and aldosterone in LIFE-Heart only (max. n=2070). All genome-wide significant loci were tested for sex interactions. Further, we tested if previously reported CAD SNPs were associated with our steroid hormone panel and investigated causal links between hormone levels and CAD status using Mendelian Randomization (MR) approaches. RESULTS: We discovered 15 novel associated loci for 17-hydroxyprogesterone, progesterone, DHEA-S, cortisol, androstenedione, and estradiol. Five of these loci relate to genes directly involved in steroid metabolism: CYP21A1, CYP11B1, CYP17A1, STS, and HSD17B12, almost completing the set of steroidogenic enzymes with genetic associations. Sexual dimorphisms were found for seven of the novel loci. Other loci correspond, e.g., to the WNT4/β-catenin pathway. MR revealed that cortisol, androstenedione, 17-hydroxyprogesterone and DHEA-S had causal effects on CAD. We also observed enrichment of cortisol and testosterone associations among known CAD hits. CONCLUSION: Our study greatly improves insight into genetic regulation of steroid hormones and their dependency on sex. These results could serve as a basis for analyzing sex-dimorphisms in other complex diseases.

Authors: J. Pott, YJ. Bae, K. Horn, A. Teren, Andreas Kühnapfel, H. Kirsten, U. Ceglarek, Markus Löffler, J. Thiery, J. Kratzsch, Markus Scholz

Date Published: 6th Jun 2019

Publication Type: Not specified

Human Diseases: coronary artery disease

Catalyzing Transcriptomics Research in Cardiovascular Disease: The CardioRNA COST Action CA17129
Genetical Statistics and Systems Biology

Abstract (Expand)

Cardiovascular disease (CVD) remains the leading cause of death worldwide and, despite continuous advances, better diagnostic and prognostic tools, as well as therapy, are needed. The human transcriptome, … which is the set of all RNA produced in a cell, is much more complex than previously thought and the lack of dialogue between researchers and industrials and consensus on guidelines to generate data make it harder to compare and reproduce results. This European Cooperation in Science and Technology (COST) Action aims to accelerate the understanding of transcriptomics in CVD and further the translation of experimental data into usable applications to improve personalized medicine in this field by creating an interdisciplinary network. It aims to provide opportunities for collaboration between stakeholders from complementary backgrounds, allowing the functions of different RNAs and their interactions to be more rapidly deciphered in the cardiovascular context for translation into the clinic, thus fostering personalized medicine and meeting a current public health challenge. Thus, this Action will advance studies on cardiovascular transcriptomics, generate innovative projects, and consolidate the leadership of European research groups in the field.COST (European Cooperation in Science and Technology) is a funding organization for research and innovation networks (www.cost.eu).

Authors: Clarissa Pedrosa da C. Gomes, Bence Ágg, Andrejaana Andova, Serdal Arslan, Andrew Baker, Monika Barteková, Dimitris Beis, Fay Betsou, Stephanie Bezzina Wettinger, Branko Bugarski, Gianluigi Condorelli, Gustavo José Justo da Silva, Sabrina Danilin, David de Gonzalo-Calvo, Alfonso Buil, Maria Carmo-Fonseca, Francisco J. Enguita, Kyriacos Felekkis, Peter Ferdinandy, Mariann Gyöngyösi, Matthias Hackl, Kanita Karaduzovic-Hadziabdic, Jan Hellemans, Stephane Heymans, Markéta Hlavackova, Morten Andre Hoydal, Aleksandra Jankovic, Amela Jusic, Dimitris Kardassis, Risto Kerkelä, Gabriela M. Kuster, Päivi Lakkisto, Przemyslaw Leszek, Mitja Lustrek, Lars Maegdefessel, Fabio Martelli, Susana Novella, Timothy O’Brien, Christos Papaneophytou, Thierry Pedrazzini, Florence Pinet, Octavian Popescu, Ines Potočnjak, Emma Robinson, Shlomo Sasson, Markus Scholz, Maya Simionescu, Monika Stoll, Zoltan V. Varga, Manlio Vinciguerra, Angela Xuereb, Mehmet Birhan Yilmaz, Costanza Emanueli, Yvan Devaux, behalf of the EU-CardioRNA COST Action on

Date Published: 1st Jun 2019

Publication Type: Journal article

A catalog of genetic loci associated with kidney function from analyses of a million individuals
Genetical Statistics and Systems Biology

Abstract (Expand)

Chronic kidney disease (CKD) is responsible for a public health burden with multi-systemic complications. Through trans-ancestry meta-analysis of genome-wide association studies of estimated glomerular … filtration rate (eGFR) and independent replication (n = 1,046,070), we identified 264 associated loci (166 new). Of these, 147 were likely to be relevant for kidney function on the basis of associations with the alternative kidney function marker blood urea nitrogen (n = 416,178). Pathway and enrichment analyses, including mouse models with renal phenotypes, support the kidney as the main target organ. A genetic risk score for lower eGFR was associated with clinically diagnosed CKD in 452,264 independent individuals. Colocalization analyses of associations with eGFR among 783,978 European-ancestry individuals and gene expression across 46 human tissues, including tubulo-interstitial and glomerular kidney compartments, identified 17 genes differentially expressed in kidney. Fine-mapping highlighted missense driver variants in 11 genes and kidney-specific regulatory variants. These results provide a comprehensive priority list of molecular targets for translational research.

Authors: Matthias Wuttke, Yong Li, Man Li, Karsten B. Sieber, Mary F. Feitosa, Mathias Gorski, Adrienne Tin, Lihua Wang, Audrey Y. Chu, Anselm Hoppmann, Holger Kirsten, Ayush Giri, Jin-Fang Chai, Gardar Sveinbjornsson, Bamidele O. Tayo, Teresa Nutile, Christian Fuchsberger, Jonathan Marten, Massimiliano Cocca, Sahar Ghasemi, Yizhe Xu, Katrin Horn, Damia Noce, Peter J. van der Most, Sanaz Sedaghat, Zhi Yu, Masato Akiyama, Saima Afaq, Tarunveer S. Ahluwalia, Peter Almgren, Najaf Amin, Johan Ärnlöv, Stephan J. L. Bakker, Nisha Bansal, Daniela Baptista, Sven Bergmann, Mary L. Biggs, Ginevra Biino, Michael Boehnke, Eric Boerwinkle, Mathilde Boissel, Erwin P. Bottinger, Thibaud S. Boutin, Hermann Brenner, Marco Brumat, Ralph Burkhardt, Adam S. Butterworth, Eric Campana, Archie Campbell, Harry Campbell, Mickaël Canouil, Robert J. Carroll, Eulalia Catamo, John C. Chambers, Miao-Ling Chee, Miao-Li Chee, Xu Chen, Ching-Yu Cheng, Yurong Cheng, Kaare Christensen, Renata Cifkova, Marina Ciullo, Maria Pina Concas, James P. Cook, Josef Coresh, Tanguy Corre, Cinzia Felicita Sala, Daniele Cusi, John Danesh, E. Warwick Daw, Martin H. de Borst, Alessandro de Grandi, Renée de Mutsert, Aiko P. J. de Vries, Frauke Degenhardt, Graciela Delgado, Ayse Demirkan, Emanuele Di Angelantonio, Katalin Dittrich, Jasmin Divers, Rajkumar Dorajoo, Kai-Uwe Eckardt, Georg Ehret, Paul Elliott, Karlhans Endlich, Michele K. Evans, Janine F. Felix, Valencia Hui Xian Foo, Oscar H. Franco, Andre Franke, Barry I. Freedman, Sandra Freitag-Wolf, Yechiel Friedlander, Philippe Froguel, Ron T. Gansevoort, He Gao, Paolo Gasparini, J. Michael Gaziano, Vilmantas Giedraitis, Christian Gieger, Giorgia Girotto, Franco Giulianini, Martin Gögele, Scott D. Gordon, Daniel F. Gudbjartsson, Vilmundur Gudnason, Toomas Haller, Pavel Hamet, Tamara B. Harris, Catharina A. Hartman, Caroline Hayward, Jacklyn N. Hellwege, Chew-Kiat Heng, Andrew A. Hicks, Edith Hofer, Wei Huang, Nina Hutri-Kähönen, Shih-Jen Hwang, M. Arfan Ikram, Olafur S. Indridason, Erik Ingelsson, Marcus Ising, Vincent W. V. Jaddoe, Johanna Jakobsdottir, Jost B. Jonas, Peter K. Joshi, Navya Shilpa Josyula, Bettina Jung, Mika Kähönen, Yoichiro Kamatani, Candace M. Kammerer, Masahiro Kanai, Mika Kastarinen, Shona M. Kerr, Chiea-Chuen Khor, Wieland Kiess, Marcus E. Kleber, Wolfgang Koenig, Jaspal S. Kooner, Antje Körner, Peter Kovacs, Aldi T. Kraja, Alena Krajcoviechova, Holly Kramer, Bernhard K. Krämer, Florian Kronenberg, Michiaki Kubo, Brigitte Kühnel, Mikko Kuokkanen, Johanna Kuusisto, Martina La Bianca, Markku Laakso, Leslie A. Lange, Carl D. Langefeld, Jeannette Jen-Mai Lee, Benjamin Lehne, Terho Lehtimäki, Wolfgang Lieb, Su-Chi Lim, Lars Lind, Cecilia M. Lindgren, Jun Liu, Jianjun Liu, Markus Loeffler, Ruth J. F. Loos, Susanne Lucae, Mary Ann Lukas, Leo-Pekka Lyytikäinen, Reedik Mägi, Patrik K. E. Magnusson, Anubha Mahajan, Nicholas G. Martin, Jade Martins, Winfried März, Deborah Mascalzoni, Koichi Matsuda, Christa Meisinger, Thomas Meitinger, Olle Melander, Andres Metspalu, Evgenia K. Mikaelsdottir, Yuri Milaneschi, Kozeta Miliku, Pashupati P. Mishra, Karen L. Mohlke, Nina Mononen, Grant W. Montgomery, Dennis O. Mook-Kanamori, Josyf C. Mychaleckyj, Girish N. Nadkarni, Mike A. Nalls, Matthias Nauck, Kjell Nikus, Boting Ning, Ilja M. Nolte, Raymond Noordam, Jeffrey O’Connell, Michelle L. O’Donoghue, Isleifur Olafsson, Albertine J. Oldehinkel, Marju Orho-Melander, Willem H. Ouwehand, Sandosh Padmanabhan, Nicholette D. Palmer, Runolfur Palsson, Brenda W. J. H. Penninx, Thomas Perls, Markus Perola, Mario Pirastu, Nicola Pirastu, Giorgio Pistis, Anna I. Podgornaia, Ozren Polasek, Belen Ponte, David J. Porteous, Tanja Poulain, Peter P. Pramstaller, Michael H. Preuss, Bram P. Prins, Michael A. Province, Ton J. Rabelink, Laura M. Raffield, Olli T. Raitakari, Dermot F. Reilly, Rainer Rettig, Myriam Rheinberger, Kenneth M. Rice, Paul M. Ridker, Fernando Rivadeneira, Federica Rizzi, David J. Roberts, Antonietta Robino, Peter Rossing, Igor Rudan, Rico Rueedi, Daniela Ruggiero, Kathleen A. Ryan, Yasaman Saba, Charumathi Sabanayagam, Veikko Salomaa, Erika Salvi, Kai-Uwe Saum, Helena Schmidt, Reinhold Schmidt, Ben Schöttker, Christina-Alexandra Schulz, Nicole Schupf, Christian M. Shaffer, Yuan Shi, Albert V. Smith, Blair H. Smith, Nicole Soranzo, Cassandra N. Spracklen, Konstantin Strauch, Heather M. Stringham, Michael Stumvoll, Per O. Svensson, Silke Szymczak, E-Shyong Tai, Salman M. Tajuddin, Nicholas Y. Q. Tan, Kent D. Taylor, Andrej Teren, Yih-Chung Tham, Joachim Thiery, Chris H. L. Thio, Hauke Thomsen, Gudmar Thorleifsson, Daniela Toniolo, Anke Tönjes, Johanne Tremblay, Ioanna Tzoulaki, André G. Uitterlinden, Simona Vaccargiu, Rob M. van Dam, Pim van der Harst, Cornelia M. van Duijn, Digna R. Velez Edward, Niek Verweij, Suzanne Vogelezang, Uwe Völker, Peter Vollenweider, Gerard Waeber, Melanie Waldenberger, Lars Wallentin, Ya Xing Wang, Chaolong Wang, Dawn M. Waterworth, Wen Bin Wei, Harvey White, John B. Whitfield, Sarah H. Wild, James F. Wilson, Mary K. Wojczynski, Charlene Wong, Tien-Yin Wong, Liang Xu, Qiong Yang, Masayuki Yasuda, Laura M. Yerges-Armstrong, Weihua Zhang, Alan B. Zonderman, Jerome I. Rotter, Murielle Bochud, Bruce M. Psaty, Veronique Vitart, James G. Wilson, Abbas Dehghan, Afshin Parsa, Daniel I. Chasman, Kevin Ho, Andrew P. Morris, Olivier Devuyst, Shreeram Akilesh, Sarah A. Pendergrass, Xueling Sim, Carsten A. Böger, Yukinori Okada, Todd L. Edwards, Harold Snieder, Kari Stefansson, Adriana M. Hung, Iris M. Heid, Markus Scholz, Alexander Teumer, Anna Köttgen, Cristian Pattaro

Date Published: 1st Jun 2019

Publication Type: Journal article

Sequential organ failure assessment score is an excellent operationalization of disease severity of adult patients with hospitalized community acquired pneumonia - results from the prospective observational PROGRESS study.
Genetical Statistics and Systems Biology

Abstract (Expand)

BACKGROUND: CAP (Community acquired pneumonia) is frequent, with a high mortality rate and a high burden on health care systems. Development of predictive biomarkers, new therapeutic concepts, and … epidemiologic research require a valid, reproducible, and quantitative measure describing CAP severity. METHODS: Using time series data of 1532 patients enrolled in the PROGRESS study, we compared putative measures of CAP severity for their utility as an operationalization. Comparison was based on ability to correctly identify patients with an objectively severe state of disease (death or need for intensive care with at least one of the following: substantial respiratory support, treatment with catecholamines, or dialysis). We considered IDSA/ATS minor criteria, CRB-65, CURB-65, Halm criteria, qSOFA, PSI, SCAP, SIRS-Score, SMART-COP, and SOFA. RESULTS: SOFA significantly outperformed other scores in correctly identifying a severe state of disease at the day of enrollment (AUC = 0.948), mainly caused by higher discriminative power at higher score values. Runners-up were the sum of IDSA/ATS minor criteria (AUC = 0.916) and SCAP (AUC = 0.868). SOFA performed similarly well on subsequent study days (all AUC > 0.9) and across age groups. In univariate and multivariate analysis, age, sex, and pack-years significantly contributed to higher SOFA values whereas antibiosis before hospitalization predicted lower SOFA. CONCLUSIONS: SOFA score can serve as an excellent operationalization of CAP severity and is proposed as endpoint for biomarker and therapeutic studies. TRIAL REGISTRATION: clinicaltrials.gov NCT02782013 , May 25, 2016, retrospectively registered.

Authors: P. Ahnert, P. Creutz, K. Horn, F. Schwarzenberger, M. Kiehntopf, H. Hossain, M. Bauer, F. M. Brunkhorst, K. Reinhart, U. Volker, T. Chakraborty, M. Witzenrath, M. Loffler, N. Suttorp, M. Scholz

Date Published: 4th Apr 2019

Publication Type: Journal article

Human Diseases: pneumonia

Association of Chromosome 9p21 with Subsequent Coronary Heart Disease Events: A GENIUS-CHD Study of Individual Participant Data
Genetical Statistics and Systems Biology

Abstract (Expand)

BACKGROUND Genetic variation at chromosome 9p21 is a recognized risk factor for coronary heart disease (CHD). However, its effect on disease progression and subsequent events is unclear, raising questions …s about its value for stratification of residual risk. METHODS A variant at chromosome 9p21 (rs1333049) was tested for association with subsequent events during follow-up in 103,357 Europeans with established CHD at baseline from the GENIUS-CHD Consortium (73.1% male, mean age 62.9 years). The primary outcome, subsequent CHD death or myocardial infarction (CHD death/MI), occurred in 13,040 of the 93,115 participants with available outcome data. Effect estimates were compared to case/control risk obtained from CARDIoGRAMPlusC4D including 47,222 CHD cases and 122,264 controls free of CHD. RESULTS Meta-analyses revealed no significant association between chromosome 9p21 and the primary outcome of CHD death/MI among those with established CHD at baseline (GENIUS-CHD OR 1.02; 95% CI 0.99-1.05). This contrasted with a strong association in CARDIoGRAMPlusC4D OR 1.20; 95% CI 1.18-1.22; p for interaction Conclusions: In contrast to studies comparing individuals with CHD to disease free controls, we found no clear association between genetic variation at chromosome 9p21 and risk of subsequent acute CHD events when all individuals had CHD at baseline. However, the association with subsequent revascularization may support the postulated mechanism of chromosome 9p21 for promoting atheroma development.

Authors: Riyaz S. Patel, Amand F. Schmidt, Vinicius Tragante, Raymond O. McCubrey, Michael V. Holmes, Laurence J. Howe, Kenan Direk, Axel Åkerblom, Karin Leander, Salim S. Virani, Karol A. Kaminski, Jochen D. Muehlschlegel, Marie-Pierre Dubé, Hooman Allayee, Peter Almgren, Maris Alver, Ekaterina V. Baranova, Hassan Behlouli, Bram Boeckx, Peter S. Braund, Lutz P. Breitling, Graciela Delgado, Nubia E. Duarte, Line Dufresne, Niclas Eriksson, Luisa Foco, Crystel M. Gijsberts, Yan Gong, Jaana Hartiala, Mahyar Heydarpour, Jaroslav A. Hubacek, Marcus Kleber, Daniel Kofink, Pekka Kuukasjärvi, Vei-Vei Lee, Andreas Leiherer, Petra A. Lenzini, Daniel Levin, Leo-Pekka Lyytikäinen, Nicola Martinelli, Ute Mons, Christopher P. Nelson, Kjell Nikus, Anna P. Pilbrow, Rafal Ploski, Yan V. Sun, Michael W. T. Tanck, W. H. Wilson Tang, Stella Trompet, Sander W. van der Laan, Jessica van Setten, Ragnar O. Vilmundarson, Chiara Viviani Anselmi, Efthymia Vlachopoulou, Eric Boerwinkle, Carlo Briguori, John F. Carlquist, Kathryn F. Carruthers, Gavino Casu, John Deanfield, Panos Deloukas, Frank Dudbridge, Natalie Fitzpatrick, Bruna Gigante, Stefan James, Marja-Liisa Lokki, Paulo A. Lotufo, Nicola Marziliano, Ify R. Mordi, Joseph B. Muhlestein, Christopher Newton-Cheh, Jan Pitha, Christoph H. Saely, Ayman Samman-Tahhan, Pratik B. Sandesara, Andrej Teren, Adam Timmis, Frans van de Werf, Els Wauters, Arthur A. M. Wilde, Ian Ford, David J. Stott, Ale Algra, Maria G. Andreassi, Diego Ardissino, Benoit J. Arsenault, Christie M. Ballantyne, Thomas O. Bergmeijer, Connie R. Bezzina, Simon C. Body, Peter Bogaty, Gert J. de Borst, Hermann Brenner, Ralph Burkhardt, Clara Carpeggiani, Gianluigi Condorelli, Rhonda M. Cooper-DeHoff, Sharon Cresci, Ulf de Faire, Robert N. Doughty, Heinz Drexel, James C. Engert, Keith A. A. Fox, Domenico Girelli, Emil Hagström, Stanley L. Hazen, Claes Held, Harry Hemingway, Imo E. Hoefer, G. Kees Hovingh, Julie A. Johnson, Pim A. de Jong, J. Wouter Jukema, Marcin P. Kaczor, Mika Kähönen, Jiri Kettner, Marek Kiliszek, Olaf H. Klungel, Bo Lagerqvist, Diether Lambrechts, Jari O. Laurikka, Terho Lehtimäki, Daniel Lindholm, B. K. Mahmoodi, Anke H. Maitland-van der Zee, Ruth McPherson, Olle Melander, Andres Metspalu, Witold Pepinski, Oliviero Olivieri, Grzegorz Opolski, Colin N. Palmer, Gerard Pasterkamp, Carl J. Pepine, Alexandre C. Pereira, Louise Pilote, Arshed A. Quyyumi, A. Mark Richards, Marek Sanak, Markus Scholz, Agneta Siegbahn, Juha Sinisalo, J. Gustav Smith, John A. Spertus, Alexandre F. R. Stewart, Wojciech Szczeklik, Anna Szpakowicz, Jurriën M. ten Berg, George Thanassoulis, Joachim Thiery, Yolanda van der Graaf, Frank L. J. Visseren, Johannes Waltenberger, Pim van der Harst, Jean-Claude Tardif, Naveed Sattar, Chim C. Lang, Guillaume Paré, James M. Brophy, Jeffrey L. Anderson, Winfried März, Lars Wallentin, Vicky A. Cameron, Benjamin D. Horne, Nilesh J. Samani, Aroon D. Hingorani, Folkert W. Asselbergs

Date Published: 1st Apr 2019

Publication Type: Journal article

Subsequent Event Risk in Individuals with Established Coronary Heart Disease: Design and Rationale of the GENIUS-CHD Consortium
Genetical Statistics and Systems Biology

Abstract (Expand)

BACKGROUND The \textquotedblGENetIcs of sUbSequent Coronary Heart Disease\textquotedbl (GENIUS-CHD) consortium was established to facilitate discovery and validation of genetic variants and biomarkers …s for risk of subsequent CHD events, in individuals with established CHD. METHODS The consortium currently includes 57 studies from 18 countries, recruiting 185,614 participants with either acute coronary syndrome, stable CHD or a mixture of both at baseline. All studies collected biological samples and followed-up study participants prospectively for subsequent events. RESULTS Enrollment into the individual studies took place between 1985 to present day with duration of follow up ranging from 9 months to 15 years. Within each study, participants with CHD are predominantly of self-reported European descent (38%-100%), mostly male (44%-91%) with mean ages at recruitment ranging from 40 to 75 years. Initial feasibility analyses, using a federated analysis approach, yielded expected associations between age (HR 1.15 95% CI 1.14-1.16) per 5-year increase, male sex (HR 1.17, 95% CI 1.13-1.21) and smoking (HR 1.43, 95% CI 1.35-1.51) with risk of subsequent CHD death or myocardial infarction, and differing associations with other individual and composite cardiovascular endpoints. CONCLUSIONS GENIUS-CHD is a global collaboration seeking to elucidate genetic and non-genetic determinants of subsequent event risk in individuals with established CHD, in order to improve residual risk prediction and identify novel drug targets for secondary prevention. Initial analyses demonstrate the feasibility and reliability of a federated analysis approach. The consortium now plans to initiate and test novel hypotheses as well as supporting replication and validation analyses for other investigators.

Authors: Riyaz Patel, Vinicius Tragante, Amand F. Schmidt, Raymond O. McCubrey, Michael V. Holmes, Laurence J. Howe, Kenan Direk, Axel Åkerblom, Karin Leander, Salim S. Virani, Karol A. Kaminski, Jochen D. Muehlschlegel, Hooman Allayee, Peter Almgren, Maris Alver, Ekaterina V. Baranova, Hassan Behlouli, Bram Boeckx, Peter S. Braund, Lutz P. Breitling, Graciela Delgado, Nubia E. Duarte, Marie-Pierre Dubé, Line Dufresne, Niclas Eriksson, Luisa Foco, Markus Scholz, Crystel M. Gijsberts, Charlotte Glinge, Yan Gong, Jaana Hartiala, Mahyar Heydarpour, Jaroslav A. Hubacek, Marcus Kleber, Daniel Kofink, Salma Kotti, Pekka Kuukasjärvi, Vei-Vei Lee, Andreas Leiherer, Petra A. Lenzini, Daniel Levin, Leo-Pekka Lyytikäinen, Nicola Martinelli, Ute Mons, Christopher P. Nelson, Kjell Nikus, Anna P. Pilbrow, Rafal Ploski, Yan V. Sun, Michael W. T. Tanck, W. H. Wilson Tang, Stella Trompet, Sander W. van der Laan, Jessica van Setten, Ragnar O. Vilmundarson, Chiara Viviani Anselmi, Efthymia Vlachopoulou, Lawien Al Ali, Eric Boerwinkle, Carlo Briguori, John F. Carlquist, Kathryn F. Carruthers, Gavino Casu, John Deanfield, Panos Deloukas, Frank Dudbridge, Thomas Engström, Natalie Fitzpatrick, Kim Fox, Bruna Gigante, Stefan James, Marja-Liisa Lokki, Paulo A. Lotufo, Nicola Marziliano, Ify R. Mordi, Joseph B. Muhlestein, Christopher Newton-Cheh, Jan Pitha, Christoph H. Saely, Ayman Samman-Tahhan, Pratik B. Sandesara, Andrej Teren, Adam Timmis, Frans van de Werf, Els Wauters, Arthur A. M. Wilde, Ian Ford, David J. Stott, Ale Algra, Maria G. Andreassi, Diego Ardissino, Benoit J. Arsenault, Christie M. Ballantyne, Thomas O. Bergmeijer, Connie R. Bezzina, Simon C. Body, Eric H. Boersma, Peter Bogaty, Michiel Bots, Hermann Brenner, Jasper J. Brugts, Ralph Burkhardt, Clara Carpeggiani, Gianluigi Condorelli, Rhonda M. Cooper-DeHoff, Sharon Cresci, Nicolas Danchin, Ulf de Faire, Robert N. Doughty, Heinz Drexel, James C. Engert, Keith A. A. Fox, Domenico Girelli, Diederick E. Grobbee, Emil Hagström, Stanley L. Hazen, Claes Held, Harry Hemingway, Imo E. Hoefer, G. Kees Hovingh, Reza Jabbari, Julie A. Johnson, J. Wouter Jukema, Marcin P. Kaczor, Mika Kähönen, Jiri Kettner, Marek Kiliszek, Olaf H. Klungel, Bo Lagerqvist, Diether Lambrechts, Jari O. Laurikka, Terho Lehtimäki, Daniel Lindholm, B. K. Mahmoodi, Anke H. Maitland-van der Zee, Ruth McPherson, Olle Melander, Andres Metspalu, Anna Niemcunowicz-Janica, Oliviero Olivieri, Grzegorz Opolski, Colin N. Palmer, Gerard Pasterkamp, Carl J. Pepine, Alexandre C. Pereira, Louise Pilote, Arshed A. Quyyumi, A. Mark Richards, Marek Sanak, Agneta Siegbahn, Tabassome Simon, Juha Sinisalo, J. Gustav Smith, John A. Spertus, Steen Stender, Alexandre F. R. Stewart, Wojciech Szczeklik, Anna Szpakowicz, Jean-Claude Tardif, Jurriën M. ten Berg, Jacob Tfelt-Hansen, George Thanassoulis, Joachim Thiery, Christian Torp-Pedersen, Yolanda van der Graaf, Frank L. J. Visseren, Johannes Waltenberger, Peter E. Weeke, Pim van der Harst, Chim C. Lang, Naveed Sattar, Vicky A. Cameron, Jeffrey L. Anderson, James M. Brophy, Guillaume Paré, Benjamin D. Horne, Winfried März, Lars Wallentin, Nilesh J. Samani, Aroon D. Hingorani, Folkert W. Asselbergs

Date Published: 1st Apr 2019

Publication Type: Journal article

Circulating Adipokine VASPIN Is Associated with Serum Lipid Profiles in Humans
Genetical Statistics and Systems Biology

Abstract (Expand)

VASPIN, visceral adipose tissue-derived serpin, is an adipokine ameliorating insulin resistance in obesity. Here, we investigated the role of VASPIN and its genetic variants in lipid metabolism. We … measured serum VASPIN concentrations by ELISA in 823 metabolically well-characterized Caucasian subjects (Sorbs from Germany). Furthermore, we genotyped 30 representative single nucleotide polymorphisms (SNP) in two independent cohorts with metabolic phenotyping, the Sorbs (N = 823) and Leipzig (N = 919), and conducted genotype-phenotype association analyses. Circulating VASPIN strongly correlated with triacylglycerol levels (TAG; p = 1.079 \times 10-11 ), and moderately with apolipoprotein A1 and low-density lipoprotein cholesterol (p = 0.026). Genetic variants in VASPIN were nominally associated with cholesterol, high-density and low-density lipoprotein (HDL-chol, LDL-chol), lipoprotein A, and apolipoprotein B as well as with TAG and free fatty acids (all p \textless 0.05 adjusted for age, sex, and body mass index [BMI]). Mendelian randomization analysis using VASPIN SNP as an instrumental variable showed borderline influence of VASPIN on LDL-chol levels (p = 0.05). Associations of VASPIN and its genetic variation with metabolic traits suggest a role of VASPIN in human lipid metabolism.

Authors: Jana Breitfeld, Norman Wiele, Beate Gutsmann, Michael Stumvoll, Matthias Blüher, Markus Scholz, Peter Kovacs, Anke Tönjes

Date Published: 18th Mar 2019

Publication Type: Journal article

Modeling individual time courses of thrombopoiesis during multi-cyclic chemotherapy.
Genetical Statistics and Systems Biology, HaematoOpt - Individualized model-based managing of the next-cycle thrombopenia of CHOEP/CHOP treated patients based on platelets dynamics during the previous cycles

Abstract (Expand)

BACKGROUND: Thrombocytopenia is a major side-effect of cytotoxic cancer therapies. The aim of precision medicine is to develop therapy modifications accounting for the individual's risk. … METHODOLOGY/PRINCIPLE FINDINGS: To solve this task, we develop an individualized bio-mechanistic model of the dynamics of bone marrow thrombopoiesis, circulating platelets and therapy effects thereon. Comprehensive biological knowledge regarding cell differentiation, amplification, apoptosis rates, transition times and corresponding regulations are translated into ordinary differential equations. A model of osteoblast/osteoclast interactions was incorporated to mechanistically describe bone marrow support of quiescent cell stages. Thrombopoietin (TPO) as a major regulator is explicitly modelled including pharmacokinetics and-dynamics of TPO injections. Effects of cytotoxic drugs are modelled by transient depletions of proliferating cells. To calibrate the model, we used population data from the literature and close-meshed individual data of N = 135 high-grade non-Hodgkin's lymphoma patients treated with CHOP-like chemotherapies. To limit the number of free parameters, several parsimony assumptions were derived from biological data and tested via Likelihood methods. Heterogeneity of patients was explained by a few model parameters. The over-fitting issue of individual parameter estimation was successfully dealt with a virtual participation of each patient in population-based experiments. The model qualitatively and quantitatively explains a number of biological observations such as the role of osteoblasts in explaining long-term toxic effects, megakaryocyte-mediated feedback on stem cells, bi-phasic stimulation of thrombopoiesis by TPO, dynamics of megakaryocyte ploidies and non-exponential platelet degradation. Almost all individual time series could be described with high precision. We demonstrated how the model can be used to provide predictions regarding individual therapy adaptations. CONCLUSIONS: We propose a mechanistic thrombopoiesis model of unprecedented comprehensiveness in both, biological mechanisms considered and experimental data sets explained. Our innovative method of parameter estimation allows robust determinations of individual parameter settings facilitating the development of individual treatment adaptations during chemotherapy.

Authors: Y. Kheifetz, M. Scholz

Date Published: 7th Mar 2019

Publication Type: Not specified

Human Diseases: blood platelet disease

Genome-wide association study identifies an acute myeloid leukemia susceptibility locus near BICRA
Genetical Statistics and Systems Biology

Abstract

Not specified

Authors: Christopher J. Walker, Christopher C. Oakes, Luke K. Genutis, Brian Giacopelli, Sandya Liyanarachchi, Deedra Nicolet, Ann-Kathrin Eisfeld, Markus Scholz, Pamela Brock, Jessica Kohlschmidt, Krzysztof Mrózek, Marius Bill, Andrew J. Carroll, Jonathan E. Kolitz, Bayard L. Powell, Eunice S. Wang, Dietger W. Niederwieser, Richard M. Stone, John C. Byrd, Sebastian Schwind, Albert de La Chapelle, Clara D. Bloomfield

Date Published: 1st Mar 2019

Publication Type: Journal article

Plasma levels of apolipoproteins C-III, A-IV, and E are independently associated with stable atherosclerotic cardiovascular disease
Genetical Statistics and Systems Biology

Abstract (Expand)

BACKGROUND AND AIMS Dyslipidemia is a major risk factor for atherosclerotic cardiovascular disease (ASCVD). As key regulators of lipoprotein metabolism, apolipoproteins (apos) are discussed as vascular …r risk factors. This study aimed to analyze associations of major plasma apos with coronary artery disease (CAD), peripheral artery disease (PAD) and carotid artery plaque (CAP) to elucidate their diagnostic potential in risk assessment. METHODS ApoA-I, apoA-II, apoA-IV, apoB-100, apoC-I, apoC-III, apoE, and apoJ were simultaneously quantified in 3 \textgreekmL EDTA-plasma by LC-MS/MS in a case-control subgroup of the Leipziger LIFE-Heart Study (N = 911). Confounder analysis with demographic, clinical covariates and serum lipids, cardiac, inflammatory, and hepatic markers were performed. Apos were associated with CAD, CAP, and PAD in a multivariate regression model. RESULTS Fasting and statin therapy showed strongest effects on apo concentrations. Inverse correlations of HDL-related apos A-I, A-II, A-IV, and C-I were observed for troponin T and interleukin 6. Concentrations of apos A-II, B-100, C-I, and E were decreased under statin therapy. After adjustment for influencing factors and related lipids, only apoB-100 (odds ratio per one SD [OR], 1.39; 95% confidence interval [CI], 1.05-1.84) was independently associated with CAD while apoA-IV (OR, 0.74; 95% CI 0.58-0.95) indicated PAD. ApoB-100 (OR, 1.55; 95% CI, 1.18-2.04), apoC-III (OR, 1.30; 95% CI, 1.06-1.58), and apoE (OR, 1.34; 95% CI, 1.13-1.58) were associated with CAP. CONCLUSIONS Triglyceride rich lipoproteins (TRLs) associated apos A-IV, B-100, C-III, and E are independently associated with stable ASCVD, providing further evidence for a potential role of TRLs in atherogenesis.

Authors: Julia Dittrich, Frank Beutner, Andrej Teren, Joachim Thiery, Ralph Burkhardt, Markus Scholz, Uta Ceglarek

Date Published: 1st Feb 2019

Publication Type: Journal article

Cyclin dependent kinase inhibitor 1 C is a female-specific marker of left ventricular function after acute myocardial infarction
Genetical Statistics and Systems Biology

Abstract (Expand)

BACKGROUND A significant proportion of patients develop left ventricular (LV) remodeling leading to heart failure after acute myocardial infarction (AMI). Being able to identify these patients would …d represent a step forward towards personalized medicine. The present study aimed to determine the ability of cyclin dependent kinase inhibitor 1C (CDKN1C) to risk stratify AMI patients, in a sex-specific manner. METHODS CDKN1C expression was measured in blood samples obtained at admission in a test cohort of 447 AMI patients and a validation cohort of 294 patients. The study end-point was LV function assessed by the ejection fraction (EF) at follow-up. RESULTS In the test cohort, CDKN1C was lower in patients with a reduced EF (\textless40%) compared to patients with preserved EF (\geq50%). This observation was specific to women. CDKN1C was a significant univariate predictor of LV function in women only. In multivariable analysis including demographic and clinical parameters, CDKN1C predicted LV function in women (odds ratio [95% confidence interval] 0.44 [0.23-0.82]) but not in men (0.90 [0.70-1.16]). Addition of CDKN1C to a multivariable clinical model reduced the Akaike information criterion, attesting for an incremental predictive value, in women (p = 0.006) but not in men (p = 0.41). Bootstrap internal validation confirmed the added value of CDKN1C in women. The female-specific predictive value of CDKN1C was validated in the independent cohort. CONCLUSION CDKN1C is a novel female-specific biomarker of LV function after AMI.

Authors: Torkia Lalem, Lu Zhang, Markus Scholz, Ralph Burkhardt, Victoria Saccheti, Andrej Teren, Joachim Thiery, Yvan Devaux

Date Published: 2019

Publication Type: Journal article

Genome-wide association study of 23,500 individuals identifies 7 loci associated with brain ventricular volume
Genetical Statistics and Systems Biology

Abstract (Expand)

The volume of the lateral ventricles (LV) increases with age and their abnormal enlargement is a key feature of several neurological and psychiatric diseases. Although lateral ventricular volume is … heritable, a comprehensive investigation of its genetic determinants is lacking. In this meta-analysis of genome-wide association studies of 23,533 healthy middle-aged to elderly individuals from 26 population-based cohorts, we identify 7 genetic loci associated with LV volume. These loci map to chromosomes 3q28, 7p22.3, 10p12.31, 11q23.1, 12q23.3, 16q24.2, and 22q13.1 and implicate pathways related to tau pathology, S1P signaling, and cytoskeleton organization. We also report a significant genetic overlap between the thalamus and LV volumes (\textgreekrgenetic = -0.59, p-value = 3.14 \times 10-6), suggesting that these brain structures may share a common biology. These genetic associations of LV volume provide insights into brain morphology.

Authors: Dina Vojinovic, Hieab H. Adams, Xueqiu Jian, Qiong Yang, Albert Vernon Smith, Joshua C. Bis, Alexander Teumer, Markus Scholz, Nicola J. Armstrong, Edith Hofer, Yasaman Saba, Michelle Luciano, Manon Bernard, Stella Trompet, Jingyun Yang, Nathan A. Gillespie, Sven J. van der Lee, Alexander Neumann, Shahzad Ahmad, Ole A. Andreassen, David Ames, Najaf Amin, Konstantinos Arfanakis, Mark E. Bastin, Diane M. Becker, Alexa S. Beiser, Frauke Beyer, Henry Brodaty, R. Nick Bryan, Robin Bülow, Anders M. Dale, Philip L. de Jager, Ian J. Deary, Charles DeCarli, Debra A. Fleischman, Rebecca F. Gottesman, Jeroen van der Grond, Vilmundur Gudnason, Tamara B. Harris, Georg Homuth, David S. Knopman, John B. Kwok, Cora E. Lewis, Shuo Li, Markus Loeffler, Oscar L. Lopez, Pauline Maillard, Hanan El Marroun, Karen A. Mather, Thomas H. Mosley, Ryan L. Muetzel, Matthias Nauck, Paul A. Nyquist, Matthew S. Panizzon, Zdenka Pausova, Bruce M. Psaty, Ken Rice, Jerome I. Rotter, Natalie Royle, Claudia L. Satizabal, Reinhold Schmidt, Peter R. Schofield, Pamela J. Schreiner, Stephen Sidney, David J. Stott, Anbupalam Thalamuthu, Andre G. Uitterlinden, Maria C. Valdés Hernández, Meike W. Vernooij, Wei Wen, Tonya White, A. Veronica Witte, Katharina Wittfeld, Margaret J. Wright, Lisa R. Yanek, Henning Tiemeier, William S. Kremen, David A. Bennett, J. Wouter Jukema, Tomas Paus, Joanna M. Wardlaw, Helena Schmidt, Perminder S. Sachdev, Arno Villringer, Hans Jörgen Grabe, W. T. Longstreth, Cornelia M. van Duijn, Lenore J. Launer, Sudha Seshadri, M. Arfan Ikram, Myriam Fornage

Date Published: 1st Dec 2018

Publication Type: Journal article

GWAS and colocalization analyses implicate carotid intima-media thickness and carotid plaque loci in cardiovascular outcomes
Genetical Statistics and Systems Biology

Abstract (Expand)

Carotid artery intima media thickness (cIMT) and carotid plaque are measures of subclinical atherosclerosis associated with ischemic stroke and coronary heart disease (CHD). Here, we undertake meta-analyses … of genome-wide association studies (GWAS) in 71,128 individuals for cIMT, and 48,434 individuals for carotid plaque traits. We identify eight novel susceptibility loci for cIMT, one independent association at the previously-identified PINX1 locus, and one novel locus for carotid plaque. Colocalization analysis with nearby vascular expression quantitative loci (cis-eQTLs) derived from arterial wall and metabolic tissues obtained from patients with CHD identifies candidate genes at two potentially additional loci, ADAMTS9 and LOXL4. LD score regression reveals significant genetic correlations between cIMT and plaque traits, and both cIMT and plaque with CHD, any stroke subtype and ischemic stroke. Our study provides insights into genes and tissue-specific regulatory mechanisms linking atherosclerosis both to its functional genomic origins and its clinical consequences in humans.

Authors: Nora Franceschini, Claudia Giambartolomei, Paul S. de Vries, Chris Finan, Joshua C. Bis, Rachael P. Huntley, Ruth C. Lovering, Salman M. Tajuddin, Thomas W. Winkler, Misa Graff, Maryam Kavousi, Caroline Dale, Albert V. Smith, Edith Hofer, Elisabeth M. van Leeuwen, Ilja M. Nolte, Lingyi Lu, Markus Scholz, Muralidharan Sargurupremraj, Niina Pitkänen, Oscar Franzén, Peter K. Joshi, Raymond Noordam, Riccardo E. Marioni, Shih-Jen Hwang, Solomon K. Musani, Ulf Schminke, Walter Palmas, Aaron Isaacs, Adolfo Correa, Alan B. Zonderman, Albert Hofman, Alexander Teumer, Amanda J. Cox, André G. Uitterlinden, Andrew Wong, Andries J. Smit, Anne B. Newman, Annie Britton, Arno Ruusalepp, Bengt Sennblad, Bo Hedblad, Bogdan Pasaniuc, Brenda W. Penninx, Carl D. Langefeld, Christina L. Wassel, Christophe Tzourio, Cristiano Fava, Damiano Baldassarre, Daniel H. O’Leary, Daniel Teupser, Diana Kuh, Elena Tremoli, Elmo Mannarino, Enzo Grossi, Eric Boerwinkle, Eric E. Schadt, Erik Ingelsson, Fabrizio Veglia, Fernando Rivadeneira, Frank Beutner, Ganesh Chauhan, Gerardo Heiss, Harold Snieder, Harry Campbell, Henry Völzke, Hugh S. Markus, Ian J. Deary, J. Wouter Jukema, Jacqueline de Graaf, Jacqueline Price, Janne Pott, Jemma C. Hopewell, Jingjing Liang, Joachim Thiery, Jorgen Engmann, Karl Gertow, Kenneth Rice, Kent D. Taylor, Klodian Dhana, Lambertus A. L. M. Kiemeney, Lars Lind, Laura M. Raffield, Lenore J. Launer, Lesca M. Holdt, Marcus Dörr, Martin Dichgans, Matthew Traylor, Matthias Sitzer, Meena Kumari, Mika Kivimaki, Mike A. Nalls, Olle Melander, Olli Raitakari, Oscar H. Franco, Oscar L. Rueda-Ochoa, Panos Roussos, Peter H. Whincup, Philippe Amouyel, Philippe Giral, Pramod Anugu, Quenna Wong, Rainer Malik, Rainer Rauramaa, Ralph Burkhardt, Rebecca Hardy, Reinhold Schmidt, Renée de Mutsert, Richard W. Morris, Rona J. Strawbridge, S. Goya Wannamethee, Sara Hägg, Sonia Shah, Stela McLachlan, Stella Trompet, Sudha Seshadri, Sudhir Kurl, Susan R. Heckbert, Susan Ring, Tamara B. Harris, Terho Lehtimäki, Tessel E. Galesloot, Tina Shah, Ulf de Faire, Vincent Plagnol, Wayne D. Rosamond, Wendy Post, Xiaofeng Zhu, Xiaoling Zhang, Xiuqing Guo, Yasaman Saba, Abbas Dehghan, Adrie Seldenrijk, Alanna C. Morrison, Anders Hamsten, Bruce M. Psaty, Cornelia M. van Duijn, Deborah A. Lawlor, Dennis O. Mook-Kanamori, Donald W. Bowden, Helena Schmidt, James F. Wilson, James G. Wilson, Jerome I. Rotter, Joanna M. Wardlaw, John Deanfield, Julian Halcox, Leo-Pekka Lyytikäinen, Markus Loeffler, Michele K. Evans, Stéphanie Debette, Steve E. Humphries, Uwe Völker, Vilmundur Gudnason, Aroon D. Hingorani, Johan L. M. Björkegren, Juan P. Casas, Christopher J. O’Donnell

Date Published: 1st Dec 2018

Publication Type: Journal article

Study of 300,486 individuals identifies 148 independent genetic loci influencing general cognitive function
Genetical Statistics and Systems Biology

Abstract (Expand)

General cognitive function is a prominent and relatively stable human trait that is associated with many important life outcomes. We combine cognitive and genetic data from the CHARGE and COGENT … consortia, and UK Biobank (total N = 300,486; age 16-102) and find 148 genome-wide significant independent loci (P \textless 5 \times 10-8) associated with general cognitive function. Within the novel genetic loci are variants associated with neurodegenerative and neurodevelopmental disorders, physical and psychiatric illnesses, and brain structure. Gene-based analyses find 709 genes associated with general cognitive function. Expression levels across the cortex are associated with general cognitive function. Using polygenic scores, up to 4.3% of variance in general cognitive function is predicted in independent samples. We detect significant genetic overlap between general cognitive function, reaction time, and many health variables including eyesight, hypertension, and longevity. In conclusion we identify novel genetic loci and pathways contributing to the heritability of general cognitive function.

Authors: Gail Davies, Max Lam, Sarah E. Harris, Joey W. Trampush, Michelle Luciano, W. David Hill, Saskia P. Hagenaars, Stuart J. Ritchie, Riccardo E. Marioni, Chloe Fawns-Ritchie, David C. M. Liewald, Judith A. Okely, Ari V. Ahola-Olli, Catriona L. K. Barnes, Lars Bertram, Joshua C. Bis, Katherine E. Burdick, Andrea Christoforou, Pamela DeRosse, Srdjan Djurovic, Thomas Espeseth, Stella Giakoumaki, Sudheer Giddaluru, Daniel E. Gustavson, Caroline Hayward, Edith Hofer, M. Arfan Ikram, Robert Karlsson, Emma Knowles, Jari Lahti, Markus Leber, Shuo Li, Karen A. Mather, Ingrid Melle, Derek Morris, Christopher Oldmeadow, Teemu Palviainen, Antony Payton, Raha Pazoki, Katja Petrovic, Chandra A. Reynolds, Muralidharan Sargurupremraj, Markus Scholz, Jennifer A. Smith, Albert V. Smith, Natalie Terzikhan, Anbupalam Thalamuthu, Stella Trompet, Sven J van der Lee, Erin B. Ware, B. Gwen Windham, Margaret J. Wright, Jingyun Yang, Jin Yu, David Ames, Najaf Amin, Philippe Amouyel, Ole A. Andreassen, Nicola J. Armstrong, Amelia A. Assareh, John R. Attia, Deborah Attix, Dimitrios Avramopoulos, David A. Bennett, Anne C. Böhmer, Patricia A. Boyle, Henry Brodaty, Harry Campbell, Tyrone D. Cannon, Elizabeth T. Cirulli, Eliza Congdon, Emily Drabant Conley, Janie Corley, Simon R. Cox, Anders M. Dale, Abbas Dehghan, Danielle Dick, Dwight Dickinson, Johan G. Eriksson, Evangelos Evangelou, Jessica D. Faul, Ian Ford, Nelson A. Freimer, He Gao, Ina Giegling, Nathan A. Gillespie, Scott D. Gordon, Rebecca F. Gottesman, Michael E. Griswold, Vilmundur Gudnason, Tamara B. Harris, Annette M. Hartmann, Alex Hatzimanolis, Gerardo Heiss, Elizabeth G. Holliday, Peter K. Joshi, Mika Kähönen, Sharon L. R. Kardia, Ida Karlsson, Luca Kleineidam, David S. Knopman, Nicole A. Kochan, Bettina Konte, John B. Kwok, Stephanie Le Hellard, Teresa Lee, Terho Lehtimäki, Shu-Chen Li, Tian Liu, Marisa Koini, Edythe London, Will T. Longstreth, Oscar L. Lopez, Anu Loukola, Tobias Luck, Astri J. Lundervold, Anders Lundquist, Leo-Pekka Lyytikäinen, Nicholas G. Martin, Grant W. Montgomery, Alison D. Murray, Anna C. Need, Raymond Noordam, Lars Nyberg, William Ollier, Goran Papenberg, Alison Pattie, Ozren Polasek, Russell A. Poldrack, Bruce M. Psaty, Simone Reppermund, Steffi G. Riedel-Heller, Richard J. Rose, Jerome I. Rotter, Panos Roussos, Suvi P. Rovio, Yasaman Saba, Fred W. Sabb, Perminder S. Sachdev, Claudia L. Satizabal, Matthias Schmid, Rodney J. Scott, Matthew A. Scult, Jeannette Simino, P. Eline Slagboom, Nikolaos Smyrnis, Aïcha Soumaré, Nikos C. Stefanis, David J. Stott, Richard E. Straub, Kjetil Sundet, Adele M. Taylor, Kent D. Taylor, Ioanna Tzoulaki, Christophe Tzourio, André Uitterlinden, Veronique Vitart, Aristotle N. Voineskos, Jaakko Kaprio, Michael Wagner, Holger Wagner, Leonie Weinhold, K. Hoyan Wen, Elisabeth Widen, Qiong Yang, Wei Zhao, Hieab H. H. Adams, Dan E. Arking, Robert M. Bilder, Panos Bitsios, Eric Boerwinkle, Ornit Chiba-Falek, Aiden Corvin, Philip L. de Jager, Stéphanie Debette, Gary Donohoe, Paul Elliott, Annette L. Fitzpatrick, Michael Gill, David C. Glahn, Sara Hägg, Narelle K. Hansell, Ahmad R. Hariri, M. Kamran Ikram, J. Wouter Jukema, Eero Vuoksimaa, Matthew C. Keller, William S. Kremen, Lenore Launer, Ulman Lindenberger, Aarno Palotie, Nancy L. Pedersen, Neil Pendleton, David J. Porteous, Katri Räikkönen, Olli T. Raitakari, Alfredo Ramirez, Ivar Reinvang, Igor Rudan, Rujescu Dan, Reinhold Schmidt, Helena Schmidt, Peter W. Schofield, Peter R. Schofield, John M. Starr, Vidar M. Steen, Julian N. Trollor, Steven T. Turner, Cornelia M. van Duijn, Arno Villringer, Daniel R. Weinberger, David R. Weir, James F. Wilson, Anil Malhotra, Andrew M. McIntosh, Catharine R. Gale, Sudha Seshadri, Thomas H. Mosley, Jan Bressler, Todd Lencz, Ian J. Deary

Date Published: 1st Dec 2018

Publication Type: Journal article

Parameters of pulse wave velocity: determinants and reference values assessed in the population-based study LIFE-Adult
Genetical Statistics and Systems Biology

Abstract (Expand)

AIMS AND BACKGROUND Parameters of arterial stiffness such as pulse wave velocity (PWV) were recently proposed as independent risk factors of cardiovascular events. We analyse three PWV parameters in …n the large population-based study LIFE-Adult to identify risk factors, normal and reference values. METHODS AND RESULTS Brachial-ankle (ba), brachial-femoral (bf) and carotid-femoral (cf) PWV assessment was performed using Vicorder device. 8509 participants aged 19-80 were analysed. PWV parameters were moderately correlated (r(ba/bf) = 0.6, r(ba/cf) = 0.46, r(bf/cf) = 0.59). Age and blood pressure are the dominant determinants of PWV parameters explaining \textgreater 18% of variability. Sex was only relevant for bfPWV and cfPWV. All further analysed cardiovascular and other risk factors are of minor importance. We provide age-dependent percentiles for the population (reference values) and for the subgroup of normotonic individuals. All percentiles show a strong increase with age. The difference between normotonic and all individuals is small for younger age groups but increases up to 1 m/s for elderly subjects. CONCLUSION Our study confirms and further underpins the strong impact of age and blood pressure on arterial stiffness and the relatively weak contribution of other factors, supporting an independent role of arterial stiffness in cardiovascular disease development. Age-dependent reference and normal values were provided on the basis of the so far largest study sample facilitating the implementation of PWV assessment in clinical practice. Due to better compliance, handling and stronger association with age and blood pressure, baPWV could serve as an alternative to cfPWV. Follow-up data are required to estimate the clinical significance of specified PWV cut-offs.

Authors: Daniel Baier, Andrej Teren, Kerstin Wirkner, Markus Loeffler, Markus Scholz

Date Published: 1st Nov 2018

Publication Type: Journal article

Prognostic and Pathogenic Role of Angiopoietin-1 and -2 in Pneumonia
Genetical Statistics and Systems Biology

Abstract (Expand)

RATIONALE During pneumonia, pathogen-host interaction evokes inflammation and lung barrier dysfunction. Tie2-activation by Angiopoietin-1 reduces, while Tie2-blockade by Angiopoietin-2 increases …s inflammation and permeability during sepsis. The role of Angiopoietin-1/-2 in pneumonia remains unidentified. OBJECTIVES To investigate the prognostic and pathogenetic impact of Angiopoietins in regulating pulmonary vascular barrier function and inflammation in bacterial pneumonia. METHODS Serum Angiopoietin levels were quantified in pneumonia patients of two independent cohorts (n=148, n=395). Human post mortem lung tissue, pneumolysin- or Angiopoietin-2-stimulated endothelial cells, isolated perfused and ventilated mouse lungs, and mice with pneumococcal pneumonia were investigated. MEASUREMENTS AND MAIN RESULTS In pneumonia patients, decreased serum Angiopoietin-1 and increased Angiopoietin-2 levels were observed as compared to healthy subjects. Higher Angiopoietin-2 serum levels were found in community-acquired pneumonia patients who died within 28 days after diagnosis compared to survivors. ROC analysis revealed improved prognostic accuracy of CURB-65 for 28-day survival, intensive care treatment and length of hospital stay if combined with Angiopoietin-2 serum levels. In vitro, pneumolysin enhanced endothelial Angiopoietin-2 release, Angiopoietin-2 increased endothelial permeability, and Angiopoietin-1 reduced pneumolysin-evoked endothelial permeability. Ventilated and perfused lungs of mice with Angiopoietin-2-knockdown showed reduced permeability upon pneumolysin stimulation. Increased pulmonary Angiopoietin-2 and reduced Angiopoietin-1 mRNA expression were observed in S. pneumoniae infected mice. Finally, Angiopoietin-1 therapy reduced inflammation and permeability in murine pneumonia. CONCLUSIONS These data suggest a central role of Angiopoietin-1/-2 in pneumonia-evoked inflammation and permeability. Increased Angiopoietin-2 serum levels predicted mortality and length of hospital stay, and Angiopoietin-1 may provide a therapeutic target for severe pneumonia.

Authors: Birgitt Gutbier, Anne-Kathrin Neuhauß, Katrin Reppe, Carolin Ehrler, Ansgar Santel, Jörg Kaufmann, Markus Scholz, Norbert Weissmann, Lars Morawietz, Timothy J. Mitchell, Stefano Aliberti, Stefan Hippenstiel, Norbert Suttorp, Martin Witzenrath

Date Published: 15th Jul 2018

Publication Type: Journal article

Common variants in the CLDN2-MORC4 and PRSS1-PRSS2 loci confer susceptibility to acute pancreatitis
Genetical Statistics and Systems Biology

Abstract (Expand)

BACKGROUND/OBJECTIVES Acute pancreatitis (AP) is one of the most common gastrointestinal disorders often requiring hospitalization. Frequent aetiologies are gallstones and alcohol abuse. In contrast …t to chronic pancreatitis (CP) few robust genetic associations have been described. Here we analysed whether common variants in the CLDN2-MORC4 and the PRSS1-PRSS2 locus that increase recurrent AP and CP risk associate with AP. METHODS We screened 1462 AP patients and 3999 controls with melting curve analysis for SNPs rs10273639 (PRSS1-PRSS2), rs7057398 (RIPPLY), and rs12688220 (MORC4). Calculations were performed for the overall group, aetiology, and gender sub-groups. To examine genotype-phenotype relationships we performed several meta-analyses. RESULTS Meta-analyses of all AP patients depicted significant (p-value \textless 0.05) associations for rs10273639 (odds ratio (OR) 0.88, 95% confidence interval (CI) 0.81-0.97, p-value 0.01), rs7057398 (OR 1.27, 95% CI 1.07-1.5, p-value 0.005), and rs12688220 (OR 1.32, 95% CI 1.12-1.56, p-value 0.001). For the different aetiology groups a significant association was shown for rs10273639 (OR 0.76, 95% CI 0.63-0.92, p-value 0.005), rs7057398 (OR 1.43, 95% CI 1.07-1.92, p-value 0.02), and rs12688220 (OR 1.44, 95% CI 1.07-1.93, p-value 0.02) in the alcoholic sub-group only. CONCLUSIONS The association of CP risk variants with different AP aetiologies, which is strongest in the alcoholic AP group, might implicate common pathomechanisms most likely between alcoholic AP and CP.

Authors: Frank Ulrich Weiss, Nico Hesselbarth, Andrea Párniczky, Dora Mosztbacher, Felix Lämmerhirt, Claudia Ruffert, Peter Kovacs, Sebastian Beer, Katharina Seltsam, Heidi Griesmann, Richard Böhme, Tom Kaune, Marcus Hollenbach, Hans-Ulrich Schulz, Peter Simon, Julia Mayerle, Markus M. Lerch, Giulia Martina Cavestro, Raffaella Alessia Zuppardo, Milena Di Leo, Pier Alberto Testoni, Ewa Malecka-Panas, Anita Gasirowska, Stanislaw Głuszek, Peter Bugert, Andrea Szentesi, Joachim Mössner, Heiko Witt, Patrick Michl, Peter Hégyi, Markus Scholz, Jonas Rosendahl

Date Published: 1st Jul 2018

Publication Type: Journal article

Genetic Regulation of PCSK9 (Proprotein Convertase Subtilisin/Kexin Type 9) Plasma Levels and Its Impact on Atherosclerotic Vascular Disease Phenotypes
Genetical Statistics and Systems Biology

Abstract (Expand)

BACKGROUND Inhibition of PCSK9 (proprotein convertase subtilisin/kexin type 9) is a novel strategy to treat hypercholesterolemia and reduce cardiovascular events. However, the potential role of circulating …g plasma PCSK9 concentrations as a diagnostic and predictive biomarker remains uncertain as of now. Here, we aimed to identify genetic variants associated with plasma PCSK9 and investigate possible causal effects on atherosclerotic vascular disease phenotypes. METHODS We performed the first genome-wide association study of plasma PCSK9 levels in a cohort of suspected and confirmed coronary artery disease (LIFE-Heart; n=3290). RESULTS Several independent variants at the PCSK9 gene locus were associated with circulating PCSK9 levels at genome-wide significance (lead SNP rs11591147, PCSK9-R46L; P=1.94\times10-17). We discovered 4 independent PCSK9 SNPs explaining 4.4% of the variance of plasma PCSK9. In addition, we identified a genome-wide significant locus at chromosome 7p22.1 (rs6957201; P=7.01\times10-9) and 7 suggestive hits (P\textless1\times10-6). Using MR (Mendelian Randomization), we detected significant causal effects of circulating PCSK9 on coronary artery disease status and severity, carotid plaques, and intima-media thickness. CONCLUSIONS Variants at the PCSK9 gene locus seem to be the major genetic determinants of plasma PCSK9 levels with 4 independent variants at the PCSK9 gene locus expressing allelic heterogeneity. The detected MR estimates support the hypothesis of a causal effect of PCSK9 on coronary artery disease and other vascular phenotypes. Other observed genetic associations for PCSK9 require validation in independent cohorts. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique Identifier: NCT00497887.

Authors: Janne Pott, Valentin Schlegel, Andrej Teren, Katrin Horn, Holger Kirsten, Christina Bluecher, Juergen Kratzsch, Markus Loeffler, Joachim Thiery, Ralph Burkhardt, Markus Scholz

Date Published: 1st May 2018

Publication Type: Journal article

Relationship between twelve adipocytokines and distinct components of the metabolic syndrome
Genetical Statistics and Systems Biology

Abstract (Expand)

Objective Adipose tissue-derived signals potentially link obesity and adipose tissue dysfunction with metabolic and cardiovascular diseases. Although some adipocytokines have been closely related to …o metabolic and cardiovascular traits, it remains open which adipocytokine or adipocytokine cluster serve as meaningful marker of metabolic syndrome (MS) components. Therefore, this study investigates the associations of twelve adipocytokines with components of the MS to identify the most relevant cytokines potentially related to specific metabolic profiles. Research Design/Methods Twelve cytokines (adiponectin, adipocyte fatty acid-binding protein [AFABP], angiopoietin-related growth factor, chemerin, fibroblast growth factor [FGF] 19, FGF21, FGF23, insulin-like growth factor-1, interleukin 10, irisin, progranulin, vaspin) were quantified in a cross-sectional cohort of 1046 subjects. Hypothesis-free cluster analysis, multivariate regression analyses with parameters of the MS, and discriminant analysis were performed to assess associations and the relative importance of each cytokine for reflecting MS and its components. Results Among the studied adipocytokines, adiponectin, AFABP, chemerin, and FGF21 showed the strongest associations with MS and several MS components in discriminant analyses and multiple regression models. For certain metabolic components, these adipocytokines were better discriminators than routine metabolic markers. Other cytokines investigated in the present cohort are less potent to discriminate between metabolically healthy and unhealthy subjects. Conclusions Adiponectin, AFABP, chemerin, and FGF21 show strongest associations with MS components in a general population suggesting that adverse adipose tissue function represents a major contributor to these metabolic abnormalities. Future prospective studies need to address the question whether these adipocytokines are able to predict the development of metabolic disease states.

Authors: Thomas Ebert, Claudia Gebhardt, Markus Scholz, Tobias Wohland, Dorit Schleinitz, Mathias Fasshauer, Matthias Blüher, Michael Stumvoll, Peter Kovacs, Anke Tönjes

Date Published: 1st Mar 2018

Publication Type: Journal article

Genome-wide meta-analysis identifies novel determinants of circulating serum progranulin.
Genetical Statistics and Systems Biology

Abstract (Expand)

Progranulin is a secreted protein with important functions in processes including immune and inflammatory response, metabolism and embryonic development. The present study aimed at identification of … genetic factors determining progranulin concentrations. We conducted a genome-wide association meta-analysis for serum progranulin in three independent cohorts from Europe: Sorbs (N = 848) and KORA (N = 1628) from Germany and PPP-Botnia (N = 335) from Finland (total N = 2811). Single nucleotide polymorphisms (SNPs) associated with progranulin levels were replicated in two additional German cohorts: LIFE-Heart Study (Leipzig; N = 967) and Metabolic Syndrome Berlin Potsdam (Berlin cohort; N = 833). We measured mRNA expression of genes in peripheral blood mononuclear cells (PBMC) by micro-arrays and performed mRNA expression quantitative trait and expression-progranulin association studies to functionally substantiate identified loci. Finally, we conducted siRNA silencing experiments in vitro to validate potential candidate genes within the associated loci. Heritability of circulating progranulin levels was estimated at 31.8% and 26.1% in the Sorbs and LIFE-Heart cohort, respectively. SNPs at three loci reached study-wide significance (rs660240 in CELSR2-PSRC1-MYBPHL-SORT1, rs4747197 in CDH23-PSAP and rs5848 in GRN) explaining 19.4%/15.0% of the variance and 61%/57% of total heritability in the Sorbs/LIFE-Heart Study. The strongest evidence for association was at rs660240 (P = 5.75 x 10-50), which was also associated with mRNA expression of PSRC1 in PBMC (P = 1.51 x 10-21). Psrc1 knockdown in murine preadipocytes led to a consecutive 30% reduction in progranulin secretion. In conclusion, the present meta-GWAS combined with mRNA expression identified three loci associated with progranulin and supports the role of PSRC1 in the regulation of progranulin secretion.

Authors: A. Tonjes, M. Scholz, J. Kruger, K. Krause, D. Schleinitz, H. Kirsten, C. Gebhardt, C. Marzi, H. Grallert, C. Ladenvall, H. Heyne, E. Laurila, J. Kriebel, C. Meisinger, W. Rathmann, C. Gieger, L. Groop, I. Prokopenko, B. Isomaa, F. Beutner, J. Kratzsch, A. Fischer-Rosinsky, A. Pfeiffer, K. Krohn, J. Spranger, J. Thiery, M. Bluher, M. Stumvoll, P. Kovacs

Date Published: 1st Feb 2018

Publication Type: Journal article

Urine Biomarkers of Tubular Renal Cell Damage for the Prediction of Acute Kidney Injury After Cardiac Surgery-A Pilot Study
Genetical Statistics and Systems Biology

Abstract (Expand)

OBJECTIVE To evaluate the perioperative course of urine levels of the renal damage biomarkers tissue inhibitor of metalloproteinase 2 (TIMP-2) and insulin-like growth factor-binding protein 7 (IGFBP7) …) and to evaluate the predictive value of elevated TIMP-2 \times IGFBP7 concentrations to predict acute kidney injury (AKI) early after cardiac on-pump surgery. DESIGN Prospective, observational cohort study. SETTING University hospital. PARTICIPANTS The study comprised 110 consecutive patients undergoing elective cardiac surgery with cardiopulmonary bypass (CPB) between January and March 2014. INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS Urinary TIMP-2 \times IGFBP7 levels were quantified using a commercially available kit at the following measurement points: before surgery, 1 hour after starting CPB, 4 hours after weaning from CPB, and 24 hours after weaning from CPB (time points 1-4). Postoperative AKI was defined according to Kidney Disease Improving Global Outcomes criteria. AKI after cardiac surgery was diagnosed in 9 patients (8%). The perioperative course of TIMP-2 \times IGFBP7 was significantly different in patients with and without postoperative AKI (p \textless 0.001). TIMP-2 \times IGFBP7 levels were significantly higher in patients with AKI 1 hour after CPB start and 24 hours after weaning from CPB (p \textless 0.05). TIMP-2 \times IGFBP7 levels \textgreater0.40 (ng/mL)(2)/1,000 measured at 1 hour after starting CPB were found to be the optimal cut-off, with a sensitivity of 0.778 and a specificity of 0.641. The negative predictive value was 0.972. CONCLUSIONS Urine levels of TIMP-2 \times IGFBP7 are predictive for AKI at an early time point (1 hour after starting CPB). Renal damage biomarkers such as TIMP-2 and IGFBP7 might be recommended as a supplement to traditionally used criteria of AKI prediction.

Authors: Tanja Mayer, Daniel Bolliger, Markus Scholz, Oliver Reuthebuch, Michael Gregor, Patrick Meier, Martin Grapow, Manfred D. Seeberger, Jens Fassl

Date Published: 1st Dec 2017

Publication Type: Journal article

Genetic correlations reveal the shared genetic architecture of transcription in human peripheral blood
Genetical Statistics and Systems Biology

Abstract (Expand)

Transcript co-expression is regulated by a combination of shared genetic and environmental factors. Here, we estimate the proportion of co-expression that is due to shared genetic variance. To do so, … we estimated the genetic correlations between each pairwise combination of 2469 transcripts that are highly heritable and expressed in whole blood in 1748 unrelated individuals of European ancestry. We identify 556 pairs with a significant genetic correlation of which 77% are located on different chromosomes, and report 934 expression quantitative trait loci, identified in an independent cohort, with significant effects on both transcripts in a genetically correlated pair. We show significant enrichment for transcription factor control and physical proximity through chromatin interactions as possible mechanisms of shared genetic control. Finally, we construct networks of interconnected transcripts and identify their underlying biological functions. Using genetic correlations to investigate transcriptional co-regulation provides valuable insight into the nature of the underlying genetic architecture of gene regulation.Covariance of gene expression pairs is due to a combination of shared genetic and environmental factors. Here the authors estimate the genetic correlation between highly heritable pairs and identify transcription factor control and chromatin interactions as possible mechanisms of correlation.

Authors: Samuel W. Lukowski, Luke R. Lloyd-Jones, Alexander Holloway, Holger Kirsten, Gibran Hemani, Jian Yang, Kerrin Small, Jing Zhao, Andres Metspalu, Emmanouil T. Dermitzakis, Greg Gibson, Timothy D. Spector, Joachim Thiery, Markus Scholz, Grant W. Montgomery, Tonu Esko, Peter M. Visscher, Joseph E. Powell

Date Published: 1st Dec 2017

Publication Type: Journal article

On the impact of relatedness on SNP association analysis
Genetical Statistics and Systems Biology

Abstract (Expand)

BACKGROUND When testing for SNP (single nucleotide polymorphism) associations in related individuals, observations are not independent. Simple linear regression assuming independent normally distributed …d residuals results in an increased type I error and the power of the test is also affected in a more complicate manner. Inflation of type I error is often successfully corrected by genomic control. However, this reduces the power of the test when relatedness is of concern. In the present paper, we derive explicit formulae to investigate how heritability and strength of relatedness contribute to variance inflation of the effect estimate of the linear model. Further, we study the consequences of variance inflation on hypothesis testing and compare the results with those of genomic control correction. We apply the developed theory to the publicly available HapMap trio data (N=129), the Sorbs (a self-contained population with N=977 characterised by a cryptic relatedness structure) and synthetic family studies with different sample sizes (ranging from N=129 to N=999) and different degrees of relatedness. RESULTS We derive explicit and easily to apply approximation formulae to estimate the impact of relatedness on the variance of the effect estimate of the linear regression model. Variance inflation increases with increasing heritability. Relatedness structure also impacts the degree of variance inflation as shown for example family structures. Variance inflation is smallest for HapMap trios, followed by a synthetic family study corresponding to the trio data but with larger sample size than HapMap. Next strongest inflation is observed for the Sorbs, and finally, for a synthetic family study with a more extreme relatedness structure but with similar sample size as the Sorbs. Type I error increases rapidly with increasing inflation. However, for smaller significance levels, power increases with increasing inflation while the opposite holds for larger significance levels. When genomic control is applied, type I error is preserved while power decreases rapidly with increasing variance inflation. CONCLUSIONS Stronger relatedness as well as higher heritability result in increased variance of the effect estimate of simple linear regression analysis. While type I error rates are generally inflated, the behaviour of power is more complex since power can be increased or reduced in dependence on relatedness and the heritability of the phenotype. Genomic control cannot be recommended to deal with inflation due to relatedness. Although it preserves type I error, the loss in power can be considerable. We provide a simple formula for estimating variance inflation given the relatedness structure and the heritability of a trait of interest. As a rule of thumb, variance inflation below 1.05 does not require correction and simple linear regression analysis is still appropriate.

Authors: Arnd Gross, Anke Tönjes, Markus Scholz

Date Published: 1st Dec 2017

Publication Type: Journal article

Sevoflurane and Isoflurane-Pharmacokinetics, Hemodynamic Stability and Cardio-protective Effects During Cardiopulmonary Bypass
Genetical Statistics and Systems Biology

Abstract

Not specified

Authors: David Freiermuth, Berend Mets, Daniel Bolliger, Oliver Reuthebuch, Thomas Doebele, Markus Scholz, Michael Gregor, Marcel Haschke, Manfred Seeberger, Jens Fassl

Date Published: 1st Dec 2017

Publication Type: Journal article

Cholesterol esterification in plasma as a biomarker for liver function and prediction of mortality
Genetical Statistics and Systems Biology

Abstract (Expand)

BACKGROUND Advanced stages of liver cirrhosis lead to a dramatically increased mortality. For valid identification of these patients suitable biomarkers are essential. The most important biomarkers for …r liver function are bilirubin and prothrombin time expressed as International Normalized Ratio (INR). However, the influence of several anticoagulants on the prothrombin time limits its diagnostic value. Aim of this study was the evaluation of cholesterol esterification (CE) fraction (esterified cholesterol vs. total cholesterol) as an alternative biomarker for liver synthesis and mortality prediction. Under physiological conditions the CE fraction in blood is closely regulated by lecithin-cholesterol acyltransferase (LCAT) which is produced in the liver. METHODS One hundred forty-two patients with liver disease clinically considered for orthotopic liver transplant for different indications were enrolled in the study. One patient was excluded because of the intake of a direct oral factor Xa inhibitor which has a strong impact on prothrombin time. RESULTS Results of CE fraction were in good agreement with INR (R(2) = 0.73; p \textless 0.001). In patients who died or survived within three months mean CE fraction was 56% vs. 74% (p \textless 0.001) and mean INR was 2.0 vs. 1.3 (p \textless 0.001), respectively. The predictive value of CE fraction for three-month mortality risk was higher compared to INR (p = 0.04). Results for one-year mortality were comparable. CONCLUSIONS The cholesterol esterification fraction is a valid biomarker for liver synthesis and allows reliable prediction of mortality. In contrast to INR, it is independent of anticoagulation and other analytical limitations of coagulation tests.

Authors: Thorsten Kaiser, Benedict Kinny-Köster, Michael Bartels, Thomas Berg, Markus Scholz, Cornelius Engelmann, Daniel Seehofer, Susen Becker, Uta Ceglarek, Joachim Thiery

Date Published: 1st Dec 2017

Publication Type: Journal article

Model-based optimization of G-CSF treatment during cytotoxic chemotherapy.
Genetical Statistics and Systems Biology

Abstract (Expand)

PURPOSE: Although G-CSF is widely used to prevent or ameliorate leukopenia during cytotoxic chemotherapies, its optimal use is still under debate and depends on many therapy parameters such as dosing … and timing of cytotoxic drugs and G-CSF, G-CSF pharmaceuticals used and individual risk factors of patients. METHODS: We integrate available biological knowledge and clinical data regarding cell kinetics of bone marrow granulopoiesis, the cytotoxic effects of chemotherapy and pharmacokinetics and pharmacodynamics of G-CSF applications (filgrastim or pegfilgrastim) into a comprehensive model. The model explains leukocyte time courses of more than 70 therapy scenarios comprising 10 different cytotoxic drugs. It is applied to develop optimized G-CSF schedules for a variety of clinical scenarios. RESULTS: Clinical trial results showed validity of model predictions regarding alternative G-CSF schedules. We propose modifications of G-CSF treatment for the chemotherapies 'BEACOPP escalated' (Hodgkin's disease), 'ETC' (breast cancer), and risk-adapted schedules for 'CHOP-14' (aggressive non-Hodgkin's lymphoma in elderly patients). CONCLUSIONS: We conclude that we established a model of human granulopoiesis under chemotherapy which allows predictions of yet untested G-CSF schedules, comparisons between them, and optimization of filgrastim and pegfilgrastim treatment. As a general rule of thumb, G-CSF treatment should not be started too early and patients could profit from filgrastim treatment continued until the end of the chemotherapy cycle.

Authors: S. Schirm, C. Engel, S. Loibl, M. Loeffler, M. Scholz

Date Published: 6th Nov 2017

Publication Type: Journal article

Growth and Final Height Among Children With Phenylketonuria
Genetical Statistics and Systems Biology

Abstract (Expand)

BACKGROUND AND OBJECTIVES Growth is an important criterion to evaluate health in childhood and adolescence, especially in patients depending on special dietary treatment. Phenylketonuria (PKU) is the …e most common inherited disease of amino acid metabolism. Patients with PKU depend on a special phenylalanine-restricted diet, low in natural protein. The study aimed to evaluate growth, growth rate, and target height in 224 patients with PKU. METHODS Retrospective, longitudinal analysis of standardized, yearly measurements of height, weight, and calculated growth rate (SD score [SDS]) of patients with PKU aged 0 to 18 years were conducted by using the national computerized CrescNet database. Inclusion was restricted to patients carried to term with a confirmed diagnosis of PKU or mild hyperphenylalaninemia determined by newborn screening and early treatment initiation. RESULTS From birth to adulthood, patients with PKU were significantly shorter than healthy German children (height SDS at 18 years: -0.882 \pm 0.108, P \textless .001). They missed their target height by 3 cm by adulthood (women: P = .02) and 5 cm (men: P = .01). In patients receiving casein hydrolysate during childhood, this was more pronounced compared with patients receiving amino acid mixtures (P \textless .001). Growth rate was significantly reduced during their first 2 years of life and in puberty (growth rate SDS: -1.1 to -0.5 m/year, P \textless .001 and -0.5; P \textless .02). CONCLUSIONS Early diagnosed, treated, and continuously monitored patients with PKU showed reduced height from birth onward. During the last 2 decades, this phenomenon attenuated, probably because of advances in PKU therapy related to protein supplements and special low-protein foods.

Authors: Alena G. Thiele, Ruth Gausche, Cornelia Lindenberg, Christoph Beger, Maria Arelin, Carmen Rohde, Ulrike Mütze, Johannes F. Weigel, Klaus Mohnike, Christoph Baerwald, Markus Scholz, Wieland Kiess, Roland Pfäffle, Skadi Beblo

Date Published: 1st Nov 2017

Publication Type: Journal article

Association between lipoprotein(a) level and type 2 diabetes: no evidence for a causal role of lipoprotein(a) and insulin
Genetical Statistics and Systems Biology

Abstract (Expand)

AIMS Inverse relationships have been described between the largely genetically determined levels of serum/plasma lipoprotein(a) [Lp(a)], type 2 diabetes (T2D) and fasting insulin. Here, we aimed to …o evaluate the nature of these relationships with respect to causality. METHODS We tested whether we could replicate the recent negative findings on causality between Lp(a) and T2D by employing the Mendelian randomization (MR) approach using cross-sectional data from three independent cohorts, Berlin Aging Study II (BASE-II; n = 2012), LIFE-Adult (n = 3281) and LIFE-Heart (n = 2816). Next, we explored another frequently discussed hypothesis in this context: Increasing insulin levels during the course of T2D disease development inhibits hepatic Lp(a) synthesis and thereby might explain the inverse Lp(a)-T2D association. We used two fasting insulin-associated variants, rs780094 and rs10195252, as instrumental variables in MR analysis of n = 4937 individuals from BASE-II and LIFE-Adult. We further investigated causality of the association between fasting insulin and Lp(a) by combined MR analysis of 12 additional SNPs in LIFE-Adult. RESULTS While an Lp(a)-T2D association was observed in the combined analysis (meta-effect of OR [95% CI] = 0.91 [0.87-0.96] per quintile, p = 1.3x10(-4)), we found no evidence of causality in the Lp(a)-T2D association (p = 0.29, fixed effect model) when using the variant rs10455872 as the instrumental variable in the MR analyses. Likewise, no evidence of a causal effect of insulin on Lp(a) levels was found. CONCLUSIONS While these results await confirmation in larger cohorts, the nature of the inverse Lp(a)-T2D association remains to be elucidated.

Authors: Nikolaus Buchmann, Markus Scholz, Christina M. Lill, Ralph Burkhardt, Rahel Eckardt, Kristina Norman, Markus Loeffler, Lars Bertram, Joachim Thiery, Elisabeth Steinhagen-Thiessen, Ilja Demuth

Date Published: 1st Nov 2017

Publication Type: Journal article

Genome-Wide Association Analysis for Severity of Coronary Artery Disease Using the Gensini Scoring System
Genetical Statistics and Systems Biology

Abstract (Expand)

Coronary artery disease (CAD) has a complex etiology involving numerous environmental and genetic factors of disease risk. To date, the genetic 9p21 locus represents the most robust genetic finding for … prevalent and incident CAD. However, limited information is available on the genetic background of the severity and distribution of CAD. CAD manifests itself as stable CAD or acute coronary syndrome. The Gensini score quantifies the extent CAD but requires coronary angiography. Here, we aimed to identify novel genetic variants associated with Gensini score severity and distribution of CAD. A two-stage approach including a discovery and a replication stage was used to assess genetic variants. In the discovery phase, a meta-analysis of genome-wide association data of 4,930 CAD-subjects assessed by the Gensini score was performed. Selected single nucleotide polymorphisms (SNPs) were replicated in 2,283 CAD-subjects by de novo genotyping. We identified genetic loci located on chromosome 2 and 9 to be associated with Gensini score severity and distribution of CAD in the discovery stage. Although the loci on chromosome 2 could not be replicated in the second stage, the known CAD-locus on chromosome 9p21, represented by rs133349, was identified and, thus, was confirmed as risk locus for CAD severity.

Authors: Tanja Zeller, Moritz Seiffert, Christian Müller, Markus Scholz, Anna Schäffer, Francisco Ojeda, Heinz Drexel, Axel Mündlein, Marcus E. Kleber, Winfried März, Christoph Sinning, Fabian J. Brunner, Christoph Waldeyer, Till Keller, Christoph H. Saely, Karsten Sydow, Joachim Thiery, Daniel Teupser, Stefan Blankenberg, Renate Schnabel

Date Published: 20th Sep 2017

Publication Type: Journal article

Validity and reliability of three-dimensional scanning compared with conventional anthropometry for children and adolescents-response to the rebuttal by Sabour
Genetical Statistics and Systems Biology

Abstract

Pediatric Research accepted article preview online, 29 March 2017. doi:10.1038/pr.2017.76.

Authors: Fabian Glock, Markus Scholz, Andreas Kuehnapfel, Wieland Kiess

Date Published: 1st Aug 2017

Publication Type: Journal article

Model-based individual managing of thrombocytopenia during multi-cyclic chemotherapy
HaematoOpt - Individualized model-based managing of the next-cycle thrombopenia of CHOEP/CHOP treated patients based on platelets dynamics during the previous cycles

Abstract (Expand)

Background: Thrombocytopenia is a major side-effect of cytotoxic cancer therapies. The aim of precision medicine is to develop therapy modifications accounting for the individual’s risk. Methodology/Principle … Findings: To solve this task, we develop an individualized bio-mechanistic model of the dynamics of bone marrow thrombopoiesis, circulating platelets and therapy effects thereon. Comprehensive biological knowledge regarding cell differentiation, amplification, apoptosis rates, transition times and corresponding regulations are translated into ordinary differential equations. A model of osteoblast/osteoclast interactions was incorporated to mechanistically describe bone marrow support of quiescent cell stages. Thrombopoietin (TPO) as a major regulator is explicitly modelled including pharmacokinetics and –dynamics of TPO injections. Effects of cytotoxic drugs are modelled by transient depletions of proliferating cells. To calibrate the model, we used population data from the literature and close-meshed individual data of N=135 high-grade non-Hodgkin’s lymphoma patients treated with CHOP-like chemotherapies. To limit the number of free parameters, several parsimony assumptions were derived from biological data and tested via Likelihood methods. Heterogeneity of patients was explained by a few model parameters. The over-fitting issue of individual parameter estimation was successfully dealt with a virtual participation of each patient in population-based experiments. The model qualitatively and quantitatively explains a number of biological observations such as the role of osteoblasts in explaining long-term toxic effects, megakaryocyte-mediated feedback on stem cells, bi-phasic stimulation of thrombopoiesis by TPO, dynamics of megakaryocyte ploidies and non-exponential platelet degradation. Almost all individual time series could be described with high precision. We demonstrated how the model can be used to provide predictions regarding individual therapy adaptations. Conclusions: We propose a mechanistic thrombopoiesis model of unprecedented comprehensiveness in both, biological mechanisms considered and experimental data sets explained. Our innovative method of parameter estimation allows robust determinations of individual parameter settings facilitating the development of individual treatment adaptations during chemotherapy.

Authors: Y. Kheifetz, Markus Scholz, Markus Löffler

Date Published: 9th Jun 2017

Publication Type: Not specified

Human Diseases: thrombocytopenia

Relations between lipoprotein(a) concentrations, LPA genetic variants, and the risk of mortality in patients with established coronary heart disease: a molecular and genetic association study.
Genetical Statistics and Systems Biology, LIFE Heart

Abstract (Expand)

BACKGROUND: Lipoprotein(a) concentrations in plasma are associated with cardiovascular risk in the general population. Whether lipoprotein(a) concentrations or LPA genetic variants predict long-term … mortality in patients with established coronary heart disease remains less clear. METHODS: We obtained data from 3313 patients with established coronary heart disease in the Ludwigshafen Risk and Cardiovascular Health (LURIC) study. We tested associations of tertiles of lipoprotein(a) concentration in plasma and two LPA single-nucleotide polymorphisms ([SNPs] rs10455872 and rs3798220) with all-cause mortality and cardiovascular mortality by Cox regression analysis and with severity of disease by generalised linear modelling, with and without adjustment for age, sex, diabetes diagnosis, systolic blood pressure, BMI, smoking status, estimated glomerular filtration rate, LDL-cholesterol concentration, and use of lipid-lowering therapy. Results for plasma lipoprotein(a) concentrations were validated in five independent studies involving 10 195 patients with established coronary heart disease. Results for genetic associations were replicated through large-scale collaborative analysis in the GENIUS-CHD consortium, comprising 106 353 patients with established coronary heart disease and 19 332 deaths in 22 studies or cohorts. FINDINGS: The median follow-up was 9.9 years. Increased severity of coronary heart disease was associated with lipoprotein(a) concentrations in plasma in the highest tertile (adjusted hazard radio [HR] 1.44, 95% CI 1.14-1.83) and the presence of either LPA SNP (1.88, 1.40-2.53). No associations were found in LURIC with all-cause mortality (highest tertile of lipoprotein(a) concentration in plasma 0.95, 0.81-1.11 and either LPA SNP 1.10, 0.92-1.31) or cardiovascular mortality (0.99, 0.81-1.2 and 1.13, 0.90-1.40, respectively) or in the validation studies. INTERPRETATION: In patients with prevalent coronary heart disease, lipoprotein(a) concentrations and genetic variants showed no associations with mortality. We conclude that these variables are not useful risk factors to measure to predict progression to death after coronary heart disease is established. FUNDING: Seventh Framework Programme for Research and Technical Development (AtheroRemo and RiskyCAD), INTERREG IV Oberrhein Programme, Deutsche Nierenstiftung, Else-Kroener Fresenius Foundation, Deutsche Stiftung fur Herzforschung, Deutsche Forschungsgemeinschaft, Saarland University, German Federal Ministry of Education and Research, Willy Robert Pitzer Foundation, and Waldburg-Zeil Clinics Isny.

Authors: S. Zewinger, M. E. Kleber, V. Tragante, R. O. McCubrey, A. F. Schmidt, K. Direk, U. Laufs, C. Werner, W. Koenig, D. Rothenbacher, U. Mons, L. P. Breitling, H. Brenner, R. T. Jennings, I. Petrakis, S. Triem, M. Klug, A. Filips, S. Blankenberg, C. Waldeyer, C. Sinning, R. B. Schnabel, K. J. Lackner, E. Vlachopoulou, O. Nygard, G. F. T. Svingen, E. R. Pedersen, G. S. Tell, J. Sinisalo, M. S. Nieminen, R. Laaksonen, S. Trompet, R. A. J. Smit, N. Sattar, J. W. Jukema, H. V. Groesdonk, G. Delgado, T. Stojakovic, A. P. Pilbrow, V. A. Cameron, A. M. Richards, R. N. Doughty, Y. Gong, R. Cooper-DeHoff, J. Johnson, M. Scholz, F. Beutner, J. Thiery, J. G. Smith, R. O. Vilmundarson, R. McPherson, A. F. R. Stewart, S. Cresci, P. A. Lenzini, J. A. Spertus, O. Olivieri, D. Girelli, N. I. Martinelli, A. Leiherer, C. H. Saely, H. Drexel, A. Mundlein, P. S. Braund, C. P. Nelson, N. J. Samani, D. Kofink, I. E. Hoefer, G. Pasterkamp, A. A. Quyyumi, Y. A. Ko, J. A. Hartiala, H. Allayee, W. H. W. Tang, S. L. Hazen, N. Eriksson, C. Held, E. Hagstrom, L. Wallentin, A. Akerblom, A. Siegbahn, I. Karp, C. Labos, L. Pilote, J. C. Engert, J. M. Brophy, G. Thanassoulis, P. Bogaty, W. Szczeklik, M. Kaczor, M. Sanak, S. S. Virani, C. M. Ballantyne, V. V. Lee, E. Boerwinkle, M. V. Holmes, B. D. Horne, A. Hingorani, F. W. Asselbergs, R. S. Patel, B. K. Kramer, H. Scharnagl, D. Fliser, W. Marz, T. Speer

Date Published: 2nd Jun 2017

Publication Type: Journal article

Validity and intraobserver reliability of three-dimensional scanning compared with conventional anthropometry for children and adolescents from a population-based cohort study
Genetical Statistics and Systems Biology

Abstract (Expand)

BACKGROUND Conventional anthropometric measurements are time consuming and require well trained medical staff. To use three-dimensional whole body laser scanning in daily clinical work, validity, and …d reliability have to be confirmed. METHODS We compared a whole body laser scanner with conventional anthropometry in a group of 473 children and adolescents from the Leipzig Research Centre for Civilization Diseases (LIFE-Child). Concordance correlation coefficients (CCC) were calculated separately for sex, weight, and age to assess validity. Overall CCC (OCCC) was used to analyze intraobserver reliability. RESULTS Body height and the circumferences of waist, hip, upper arm, and calf had an \textquotedblexcellent\textquotedbl (CCC ≥0.9); neck and thigh circumference, a \textquotedblgood\textquotedbl (CCC ≥0.7); and head circumference, a \textquotedbllow\textquotedbl (CCC \textless 0.5) degree of concordance over the complete study population. We observed dependencies of validity on sex, weight, and age. Intraobserver reliability of both techniques is \textquotedblexcellent\textquotedbl (OCCC ≥0.9). CONCLUSION Scanning is faster, requires less intensive staff training and provides more information. It can be used in an epidemiologic setting with children and adolescents but some measurements should be considered with caution due to reduced agreement with conventional anthropometry.

Authors: Fabian Glock, Mandy Vogel, Stephanie Naumann, Andreas Kuehnapfel, Markus Scholz, Andreas Hiemisch, Toralf Kirsten, Kristin Rieger, Antje Koerner, Markus Loeffler, Wieland Kiess

Date Published: 1st May 2017

Publication Type: Journal article

Low sphingosine-1-phosphate plasma levels are predictive for increased mortality in patients with liver cirrhosis
Genetical Statistics and Systems Biology

Abstract (Expand)

BACKGROUND & AIM: The association of circulating sphingosine-1-phosphate (S1P), a bioactive lipid involved in various cellular processes, and related metabolites such as sphinganine-1-phosphate … (SA1P) and sphingosine (SPH) with mortality in patients with end-stage liver disease is investigated in the presented study. S1P as a bioactive lipid mediator, is involved in several cellular processes, however, in end-stage liver disease its role is not understood. METHODS: The study cohort consisted of 95 patients with end-stage liver disease and available information on one-year outcome. The median MELD (Model for end-stage liver disease) score was 12.41 (Range 6.43-39.63). The quantification of sphingolipids in citrated plasma specimen was performed after methanolic protein precipitation followed by hydrophilic interaction liquid chromatography and tandem mass spectrometric detection. RESULTS: S1P and SA1P displayed significant correlations with the MELD score. Patients with circulating S1P levels below the lowest tertile (110.68 ng/ml) showed the poorest one-year survival rate of only 57.1%, whereas one-year survival rate in patients with S1P plasma levels above 165.67 ng/ml was 93.8%. In a multivariate cox regression analysis including platelet counts, concentrations of hemoglobin and MELD score, S1P remained a significant predictor for three-month and one-year mortality. CONCLUSIONS: Low plasma S1P concentrations are highly significantly associated with prognosis in end-stage liver disease. This association is independent of the stage of liver disease. Further studies should be performed to investigate S1P, its role in the pathophysiology of liver diseases and its potential for therapeutic interventions.

Authors: Susen Becker, Benedict Kinny-Koster, Michael Bartels, Markus Scholz, Daniel Seehofer, Thomas Berg, Cornelius Engelmann, Joachim Thiery, Uta Ceglarek, Thorsten Kaiser

Date Published: 23rd Mar 2017

Publication Type: Journal article

On the Conditional Power in Survival Time Analysis Considering Cure Fractions.
Genetical Statistics and Systems Biology

Abstract (Expand)

Conditional power of survival endpoints at interim analyses can support decisions on continuing a trial or stopping it for futility. When a cure fraction becomes apparent, conditional power cannot be … calculated accurately using simple survival models, e.g. the exponential model. Non-mixture models consider such cure fractions. In this paper, we derive conditional power functions for non-mixture models, namely the non-mixture exponential, the non-mixture Weibull, and the non-mixture Gamma models. Formulae were implemented in the R package CP. For an example data set of a clinical trial, we calculated conditional power under the non-mixture models and compared results with those under the simple exponential model.

Authors: A. Kuehnapfel, F. Schwarzenberger, M. Scholz

Date Published: 17th Mar 2017

Publication Type: Journal article

Genome-wide meta-analysis identifies novel loci of plaque burden in carotid artery.
Genetical Statistics and Systems Biology

Abstract (Expand)

BACKGROUND AND AIMS: Carotid artery plaque is an established marker of subclinical atherosclerosis and common patho-mechanisms with coronary artery disease (CAD) are hypothesized. We aimed to identify … genetic variants associated with carotid plaque and to examine the potential shared genetic basis with CAD. METHODS: After investigating the reliability of plaque detection, we performed a genome-wide meta-association study in two independent cohorts (LIFE-Adult, n = 4037 and LIFE-Heart, n = 3152) for carotid plaque score (PS), defined as the sum of the plaque load of common carotid artery and carotid bulb. Further, we analyzed whether previously reported CAD and stroke loci were also associated with PS. RESULTS: We identified two loci with genome-wide significance for PS. One locus is the known CAD-locus at chromosome 9p21 (lead SNP rs9644862, p = 8.73 x 10(-12)). We also describe a novel locus on chromosome 10q24 within the SFXN2 gene as the most probable candidate (lead SNP rs2902548, p = 1.97 x 10(-8)). In addition, 17 out of 58 known CAD loci and six of 17 known stroke loci were associated with PS at a nominal level of significance. CONCLUSIONS: We showed that PS is a reliable trait to analyze genetics of atherosclerosis. Two new loci of genome-wide significant association with PS were found. The observed non-random overlap of CAD and PS associations strengthens the hypothesis of a shared genetic basis for these atherosclerotic manifestations.

Authors: J. Pott, R. Burkhardt, F. Beutner, K. Horn, A. Teren, H. Kirsten, L. M. Holdt, G. Schuler, D. Teupser, M. Loeffler, J. Thiery, M. Scholz

Date Published: 11th Mar 2017

Publication Type: Journal article

Human Diseases: atherosclerosis

Alteration of Multiple Leukocyte Gene Expression Networks is Linked with Magnetic Resonance Markers of Prognosis After Acute ST-Elevation Myocardial Infarction.
LIFE Heart

Abstract (Expand)

Prognostic relevant pathways of leukocyte involvement in human myocardial ischemic-reperfusion injury are largely unknown. We enrolled 136 patients with ST-elevation myocardial infarction (STEMI) after … primary angioplasty within 12 h after onset of symptoms. Following reperfusion, whole blood was collected within a median time interval of 20 h (interquartile range: 15-25 h) for genome-wide gene expression analysis. Subsequent CMR scans were performed using a standard protocol to determine infarct size (IS), area at risk (AAR), myocardial salvage index (MSI) and the extent of late microvascular obstruction (lateMO). We found 398 genes associated with lateMO and two genes with IS. Neither AAR, nor MSI showed significant correlations with gene expression. Genes correlating with lateMO were strongly related to several canonical pathways, including positive regulation of T-cell activation (p = 3.44 x 10(-5)), and regulation of inflammatory response (p = 1.86 x 10(-3)). Network analysis of multiple gene expression alterations associated with larger lateMO identified the following functional consequences: facilitated utilisation and decreased concentration of free fatty acid, repressed cell differentiation, enhanced phagocyte movement, increased cell death, vascular disease and compensatory vasculogenesis. In conclusion, the extent of lateMO after acute, reperfused STEMI correlated with altered activation of multiple genes related to fatty acid utilisation, lymphocyte differentiation, phagocyte mobilisation, cell survival, and vascular dysfunction.

Authors: A. Teren, H. Kirsten, F. Beutner, M. Scholz, L. M. Holdt, D. Teupser, M. Gutberlet, J. Thiery, G. Schuler, I. Eitel

Date Published: 3rd Feb 2017

Publication Type: Journal article

Human Diseases: myocardial infarction

Body surface assessment with 3D laser-based anthropometry: reliability, validation, and improvement of empirical surface formulae.
Genetical Statistics and Systems Biology

Abstract (Expand)

PURPOSE Body surface area is a physiological quantity relevant for many medical applications. In clinical practice, it is determined by empirical formulae. 3D laser-based anthropometry provides an easy …y and effective way to measure body surface area but is not ubiquitously available. We used data from laser-based anthropometry from a population-based study to assess validity of published and commonly used empirical formulae. METHODS We performed a large population-based study on adults collecting classical anthropometric measurements and 3D body surface assessments (N = 1435). We determined reliability of the 3D body surface assessment and validity of 18 different empirical formulae proposed in the literature. The performance of these formulae is studied in subsets of sex and BMI. Finally, improvements of parameter settings of formulae and adjustments for sex and BMI were considered. RESULTS 3D body surface measurements show excellent intra- and inter-rater reliability of 0.998 (overall concordance correlation coefficient, OCCC was used as measure of agreement). Empirical formulae of Fujimoto and Watanabe, Shuter and Aslani and Sendroy and Cecchini performed best with excellent concordance with OCCC \textgreater 0.949 even in subgroups of sex and BMI. Re-parametrization of formulae and adjustment for sex and BMI slightly improved results. CONCLUSION In adults, 3D laser-based body surface assessment is a reliable alternative to estimation by empirical formulae. However, there are empirical formulae showing excellent results even in subgroups of sex and BMI with only little room for improvement.

Authors: Andreas Kuehnapfel, Peter Ahnert, Markus Loeffler, Markus Scholz

Date Published: 27th Jan 2017

Publication Type: Journal article

PROGRESS - prospective observational study on hospitalized community acquired pneumonia
Genetical Statistics and Systems Biology

Abstract (Expand)

BACKGROUND Community acquired pneumonia (CAP) is a high incidence disease resulting in about 260,000 hospital admissions per year in Germany, more than myocardial infarction or stroke. Worldwide, CAP …P is the most frequent infectious disease with high lethality ranging from 1.2 % in those 20-29 years old to over 10 % in patients older than 70 years, even in industrial nations. CAP poses numerous medical challenges, which the PROGRESS (Pneumonia Research Network on Genetic Resistance and Susceptibility for the Evolution of Severe Sepsis) network aims to tackle: Operationalization of disease severity throughout the course of disease, outcome prediction for hospitalized patients and prediction of transitions from uncomplicated CAP to severe CAP, and finally, to CAP with sepsis and organ failure as a life-threatening condition. It is a major aim of PROGRESS to understand and predict patient heterogeneity regarding outcome in the hospital and to develop novel treatment concepts. METHODS PROGRESS was designed as a clinical, observational, multi-center study of patients with CAP requiring hospitalization. More than 1600 patients selected for low burden of co-morbidities have been enrolled, aiming at a total of 3000. Course of disease, along with therapy, was closely monitored by daily assessments and long-term follow-up. Daily blood samples allow in depth molecular-genetic characterization of patients. We established a well-organized workflow for sample logistics and a comprehensive data management system to collect and manage data from more than 50 study centers in Germany and Austria. Samples are stored in a central biobank and clinical data are stored in a central data base which also integrates all data from molecular assessments. DISCUSSION With the PROGRESS study, we established a comprehensive data base of high quality clinical and molecular data allowing investigation of pressing research questions regarding CAP. In-depth molecular characterization will contribute to the discovery of disease mechanisms and establishment of diagnostic and predictive biomarkers. A strength of PROGRESS is the focus on younger patients with low burden of co-morbidities, allowing a more direct look at host biology with less confounding. As a resulting limitation, insights from PROGRESS will require validation in representative patient cohorts to assess clinical utility. TRIAL REGISTRATION The PROGRESS study was retrospectively registered on May 24(th), 2016 with ClinicalTrials.gov: NCT02782013.

Authors: Peter Ahnert, Petra Creutz, Markus Scholz, Hartwig Schütte, Christoph Engel, Hamid Hossain, Trinad Chakraborty, Michael Bauer, Michael Kiehntopf, Uwe Völker, Sven Hammerschmidt, Markus Loeffler, Norbert Suttorp

Date Published: 1st Dec 2016

Publication Type: Journal article

Comparing performance of modern genotype imputation methods in different ethnicities
Genetical Statistics and Systems Biology

Abstract (Expand)

A variety of modern software packages are available for genotype imputation relying on advanced concepts such as pre-phasing of the target dataset or utilization of admixed reference panels. In this … study, we performed a comprehensive evaluation of the accuracy of modern imputation methods on the basis of the publicly available POPRES samples. Good quality genotypes were masked and re-imputed by different imputation frameworks: namely MaCH, IMPUTE2, MaCH-Minimac, SHAPEIT-IMPUTE2 and MaCH-Admix. Results were compared to evaluate the relative merit of pre-phasing and the usage of admixed references. We showed that the pre-phasing framework SHAPEIT-IMPUTE2 can overestimate the certainty of genotype distributions resulting in the lowest percentage of correctly imputed genotypes in our case. MaCH-Minimac performed better than SHAPEIT-IMPUTE2. Pre-phasing always reduced imputation accuracy. IMPUTE2 and MaCH-Admix, both relying on admixed-reference panels, showed comparable results. MaCH showed superior results if well-matched references were available (Nei’s GST ≤ 0.010). For small to medium datasets, frameworks using genetically closest reference panel are recommended if the genetic distance between target and reference data set is small. Our results are valid for small to medium data sets. As shown on a larger data set of population based German samples, the disadvantage of pre-phasing decreases for larger sample sizes.

Authors: Nab Raj Roshyara, Katrin Horn, Holger Kirsten, Peter Ahnert, Markus Scholz

Date Published: 1st Dec 2016

Publication Type: Journal article

Sevoflurane and Isoflurane-Pharmacokinetics, Hemodynamic Stability, and Cardioprotective Effects During Cardiopulmonary Bypass
Genetical Statistics and Systems Biology

Abstract (Expand)

OBJECTIVES This study aimed to evaluate the pharmacokinetic profiles of sevoflurane and isoflurane during use of minimized extracorporeal circulation to perform coronary artery bypass graft surgery. …. Furthermore, cardiovascular stability during bypass and the postoperative release of troponins were evaluated. DESIGN Prospective, randomized study. SETTING University hospital. PARTICIPANTS The study comprised 31 adult patients undergoing coronary artery bypass grafting. INTERVENTIONS The pharmacokinetic measurements of the concentration of the volatile anesthetics in the arterial and venous blood, air inlet, air outlet, and gas exhaust of the extracorporeal circulation were recorded. Secondary end-points were cardiovascular stability during bypass, amount of postoperative release of troponin, time to extubation, time to discharge from the intensive care unit and the hospital, and 30-day mortality. MEASUREMENTS AND MAIN RESULTS Thirty patients completed the protocol. The pharmacokinetics of isoflurane and sevoflurane were almost identical, with a rapid wash-in (time to reach 50% of arterial steady state) concentration of 0.87\pm0.97 minutes and 1.14\pm0.35 minutes for isoflurane and sevoflurane, respectively, and a biphasic venous elimination with a terminal half-life of approximately 10 minutes for both compounds. There was a correlation between the gas inlet and the gas exhaust of the extracorporeal circulation. No difference in cardiovascular stability was found. High-sensitivity troponin concentrations on the first postoperative morning were 0.355\pm0.312 µg/mL and 0.225\pm0.111 µg/mL in the isoflurane and sevoflurane groups, respectively (p = 0.147). CONCLUSIONS The study found similar pharmacokinetics regarding wash-in and wash-out for sevoflurane and isoflurane. In addition, no difference in cardiovascular stability was found. The markers of cardiac damage were not different between the two anesthetics. Based on these data, sevoflurane and isoflurane might be used equivalently in patients undergoing coronary artery bypass graft surgery with extracorporeal circulation.

Authors: David Freiermuth, Berend Mets, Daniel Bolliger, Oliver Reuthebuch, Thomas Doebele, Markus Scholz, Michael Gregor, Matthias Haschke, Manfred Daniel Seeberger, Jens Fassl

Date Published: 1st Dec 2016

Publication Type: Journal article

Circular non-coding RNA ANRIL modulates ribosomal RNA maturation and atherosclerosis in humans
Genetical Statistics and Systems Biology

Abstract (Expand)

Circular RNAs (circRNAs) are broadly expressed in eukaryotic cells, but their molecular mechanism in human disease remains obscure. Here we show that circular antisense non-coding RNA in the INK4 locus … (circANRIL), which is transcribed at a locus of atherosclerotic cardiovascular disease on chromosome 9p21, confers atheroprotection by controlling ribosomal RNA (rRNA) maturation and modulating pathways of atherogenesis. CircANRIL binds to pescadillo homologue 1 (PES1), an essential 60S-preribosomal assembly factor, thereby impairing exonuclease-mediated pre-rRNA processing and ribosome biogenesis in vascular smooth muscle cells and macrophages. As a consequence, circANRIL induces nucleolar stress and p53 activation, resulting in the induction of apoptosis and inhibition of proliferation, which are key cell functions in atherosclerosis. Collectively, these findings identify circANRIL as a prototype of a circRNA regulating ribosome biogenesis and conferring atheroprotection, thereby showing that circularization of long non-coding RNAs may alter RNA function and protect from human disease.

Authors: Lesca M. Holdt, Anika Stahringer, Kristina Sass, Garwin Pichler, Nils A. Kulak, Wolfgang Wilfert, Alexander Kohlmaier, Andreas Herbst, Bernd H. Northoff, Alexandros Nicolaou, Gabor Gäbel, Frank Beutner, Markus Scholz, Joachim Thiery, Kiran Musunuru, Knut Krohn, Matthias Mann, Daniel Teupser

Date Published: 1st Nov 2016

Publication Type: Journal article

No Association of Coronary Artery Disease with X-Chromosomal Variants in Comprehensive International Meta-Analysis.
Genetical Statistics and Systems Biology, LIFE Heart

Abstract (Expand)

In recent years, genome-wide association studies have identified 58 independent risk loci for coronary artery disease (CAD) on the autosome. However, due to the sex-specific data structure of the X … chromosome, it has been excluded from most of these analyses. While females have 2 copies of chromosome X, males have only one. Also, one of the female X chromosomes may be inactivated. Therefore, special test statistics and quality control procedures are required. Thus, little is known about the role of X-chromosomal variants in CAD. To fill this gap, we conducted a comprehensive X-chromosome-wide meta-analysis including more than 43,000 CAD cases and 58,000 controls from 35 international study cohorts. For quality control, sex-specific filters were used to adequately take the special structure of X-chromosomal data into account. For single study analyses, several logistic regression models were calculated allowing for inactivation of one female X-chromosome, adjusting for sex and investigating interactions between sex and genetic variants. Then, meta-analyses including all 35 studies were conducted using random effects models. None of the investigated models revealed genome-wide significant associations for any variant. Although we analyzed the largest-to-date sample, currently available methods were not able to detect any associations of X-chromosomal variants with CAD.

Authors: C. Loley, M. Alver, T. L. Assimes, A. Bjonnes, A. Goel, S. Gustafsson, J. Hernesniemi, J. C. Hopewell, S. Kanoni, M. E. Kleber, K. W. Lau, Y. Lu, L. P. Lyytikainen, C. P. Nelson, M. Nikpay, L. Qu, E. Salfati, M. Scholz, T. Tukiainen, C. Willenborg, H. H. Won, L. Zeng, W. Zhang, S. S. Anand, F. Beutner, E. P. Bottinger, R. Clarke, G. Dedoussis, R. Do, T. Esko, M. Eskola, M. Farrall, D. Gauguier, V. Giedraitis, C. B. Granger, A. S. Hall, A. Hamsten, S. L. Hazen, J. Huang, M. Kahonen, T. Kyriakou, R. Laaksonen, L. Lind, C. Lindgren, P. K. Magnusson, E. Marouli, E. Mihailov, A. P. Morris, K. Nikus, N. Pedersen, L. Rallidis, V. Salomaa, S. H. Shah, A. F. Stewart, J. R. Thompson, P. A. Zalloua, J. C. Chambers, R. Collins, E. Ingelsson, C. Iribarren, P. J. Karhunen, J. S. Kooner, T. Lehtimaki, R. J. Loos, W. Marz, R. McPherson, A. Metspalu, M. P. Reilly, S. Ripatti, D. K. Sanghera, J. Thiery, H. Watkins, P. Deloukas, S. Kathiresan, N. J. Samani, H. Schunkert, J. Erdmann, I. R. Konig

Date Published: 12th Oct 2016

Publication Type: Journal article

Human Diseases: coronary artery disease

Genetic Factors of the Disease Course after Sepsis: A Genome-Wide Study for 28Day Mortality
Genetical Statistics and Systems Biology

Abstract (Expand)

Sepsis is the dysregulated host response to an infection which leads to life-threatening organ dysfunction that varies by host genomic factors. We conducted a genome-wide association study (GWAS) in … 740 adult septic patients and focused on 28day mortality as outcome. Variants with suggestive evidence for an association (p\textless/=10-5) were validated in two additional GWA studies (n=3470) and gene coding regions related to the variants were assessed in an independent exome sequencing study (n=74). In the discovery GWAS, we identified 243 autosomal variants which clustered in 14 loci (p\textless/=10-5). The best association signal (rs117983287; p=8.16x10-8) was observed for a missense variant located at chromosome 9q21.2 in the VPS13A gene. VPS13A was further supported by additional GWAS (p=0.03) and sequencing data (p=0.04). Furthermore, CRISPLD2 (p=5.99x10-6) and a region on chromosome 13q21.33 (p=3.34x10-7) were supported by both our data and external biological evidence. We found 14 loci with suggestive evidence for an association with 28day mortality and found supportive, converging evidence for three of them in independent data sets. Elucidating the underlying biological mechanisms of VPS13A, CRISPLD2, and the chromosome 13 locus should be a focus of future research activities.   Sepsis is the dysregulated host response to an infection which leads to life-threatening organ dysfunction that varies by host genomic factors. We conducted a genome-wide association study (GWAS) in 740 adult septic patients and focused on 28day mortality as outcome. Variants with suggestive evidence for an association (p\textless/=10-5) were validated in two additional GWA studies (n=3470) and gene coding regions related to the variants were assessed in an independent exome sequencing study (n=74). In the discovery GWAS, we identified 243 autosomal variants which clustered in 14 loci (p\textless/=10-5). The best association signal (rs117983287; p=8.16x10-8) was observed for a missense variant located at chromosome 9q21.2 in the VPS13A gene. VPS13A was further supported by additional GWAS (p=0.03) and sequencing data (p=0.04). Furthermore, CRISPLD2 (p=5.99x10-6) and a region on chromosome 13q21.33 (p=3.34x10-7) were supported by both our data and external biological evidence. We found 14 loci with suggestive evidence for an association with 28day mortality and found supportive, converging evidence for three of them in independent data sets. Elucidating the underlying biological mechanisms of VPS13A, CRISPLD2, and the chromosome 13 locus should be a focus of future research activities. //  Sepsis is the dysregulated host response to an infection which leads to life-threatening organ dysfunction that varies by host genomic factors. We conducted a genome-wide association study (GWAS) in 740 adult septic patients and focused on 28day mortality as outcome. Variants with suggestive evidence for an association (p\textless/=10-5) were validated in two additional GWA studies (n=3470) and gene coding regions related to the variants were assessed in an independent exome sequencing study (n=74). In the discovery GWAS, we identified 243 autosomal variants which clustered in 14 loci (p\textless/=10-5). The best association signal (rs117983287; p=8.16x10-8) was observed for a missense variant located at chromosome 9q21.2 in the VPS13A gene. VPS13A was further supported by additional GWAS (p=0.03) and sequencing data (p=0.04). Furthermore, CRISPLD2 (p=5.99x10-6) and a region on chromosome 13q21.33 (p=3.34x10-7) were supported by both our data and external biological evidence. We found 14 loci with suggestive evidence for an association with 28day mortality and found supportive, converging evidence for three of them in independent data sets. Elucidating the underlying biological mechanisms of VPS13A, CRISPLD2, and the chromosome 13 locus should be a focus of future research activities.

Authors: Andre Scherag, Franziska Schoneweck, Miriam Kesselmeier, Stefan Taudien, Matthias Platzer, Marius Felder, Christoph Sponholz, Anna Rautanen, Adrian V. S. Hill, Charles J. Hinds, Hamid Hossain, Norbert Suttorp, Oliver Kurzai, Hortense Slevogt, Evangelos J. Giamarellos-Bourboulis, Apostolos Armaganidis, Evelyn Trips, Markus Scholz, Frank M. Brunkhorst

Date Published: 1st Oct 2016

Publication Type: Journal article

Myocardial Infarction-Associated Circular RNA Predicting Left Ventricular Dysfunction.
Genetical Statistics and Systems Biology, LIFE Heart

Abstract

Not specified

Authors: M. Vausort, A. Salgado-Somoza, L. Zhang, P. Leszek, M. Scholz, A. Teren, R. Burkhardt, J. Thiery, D. R. Wagner, Y. Devaux

Date Published: 13th Sep 2016

Publication Type: Journal article

Human Diseases: left ventricular noncompaction, myocardial infarction

FTO Obesity Risk Variants Are Linked to Adipocyte IRX3 Expression and BMI of Children - Relevance of FTO Variants to Defend Body Weight in Lean Children?
Genetical Statistics and Systems Biology

Abstract (Expand)

BACKGROUND Genome-wide association studies have identified variants within the FTO (fat mass and obesity associated) locus as the strongest predictors of obesity amongst all obesity-associated gene …e loci. Recent evidence suggests that variants in FTO directly affect human adipocyte function through targeting IRX3 and IRX5 and thermogenesis regulation. AIM We addressed the relevance of this proposed FTO-IRX pathway in adipose tissue (AT) of children. RESULTS Expression of IRX3 was higher in adipocytes compared to SVF. We found increased adipocyte-specific expression of IRX3 and IRX5 with the presence of the FTO risk haplotype in lean children, whereas it was unaffected by risk variants in obese peers. We further show that IRX3 expression was elevated in isolated adipocytes and AT of lean compared to obese children, particularly in UCP1-negative adipocytes, and inversely correlated with BMI SDS. Independent of BMI, IRX3 expression in adipocytes was significantly related to adipocyte hypertrophy, and subsequent associations with AT inflammation and HOMA-IR in the children. CONCLUSION One interpretation of our observation of FTO risk variants linked to IRX3 expression and adipocyte size restricted to lean children, along with the decreased IRX3 expression in obese compared to lean peers, may reflect a defense mechanism for protecting body-weight, which is pertinent for lean children.

Authors: Kathrin Landgraf, Markus Scholz, Peter Kovacs, Wieland Kiess, Antje Körner

Date Published: 25th Aug 2016

Publication Type: Journal article

Comparing Measures of Association in 2x2 Probability Tables
Genetical Statistics and Systems Biology

Abstract

Not specified

Authors: Dirk Hasenclever, Markus Scholz

Date Published: 23rd Aug 2016

Publication Type: Journal article

Plasma Amino Acid Concentrations Predict Mortality in Patients with End-Stage Liver Disease
Genetical Statistics and Systems Biology

Abstract (Expand)

BACKGROUND The liver plays a key role in amino acid metabolism. In former studies, a ratio between branched-chain and aromatic amino acids (Fischer’s ratio) revealed associations with hepatic encephalopathy. …. Furthermore, low concentrations of branched-chain amino acids were linked to sarcopenia in literature. Encephalopathy and sarcopenia are known to dramatically worsen the prognosis. Aim of this study was to investigate a complex panel of plasma amino acids in the context of mortality in patients with end-stage liver disease. METHODS 166 patients evaluated for orthotopic liver transplantation were included. 19 amino acids were measured from citrated plasma samples using mass spectrometry. We performed survival analysis for plasma amino acid constellations and examined the relationship to established mortality predictors. RESULTS 33/166 (19.9%) patients died during follow-up. Lower values of valine (p\textless0.001), Fischer’s ratio (p\textless0.001) and valine to phenylalanine ratio (p\textless0.001) and higher values of phenylalanine (p\textless0.05) and tyrosine (p\textless0.05) were significantly associated with mortality. When divided in three groups, the tertiles discriminated cumulative survival for valine (p = 0.016), phenylalanine (p = 0.024) and in particular for valine to phenylalanine ratio (p = 0.003) and Fischer’s ratio (p = 0.005). Parameters were also significantly correlated with MELD and MELD-Na score. CONCLUSIONS Amino acids in plasma are valuable biomarkers to determine increased risk of mortality in patients with end-stage liver disease. In particular, valine concentrations and constellations composed of branched-chain and aromatic amino acids were strongly associated with prognosis. Due to their pathophysiological importance, the identified amino acids could be used to examine individual dietary recommendations to serve as potential therapeutic targets.

Authors: Benedict Kinny-Köster, Michael Bartels, Susen Becker, Markus Scholz, Joachim Thiery, Uta Ceglarek, Thorsten Kaiser

Date Published: 13th Jul 2016

Publication Type: Journal article

A Biomathematical Model of Pneumococcal Lung Infection and Antibiotic Treatment in Mice
Genetical Statistics and Systems Biology

Abstract (Expand)

Pneumonia is considered to be one of the leading causes of death worldwide. The outcome depends on both, proper antibiotic treatment and the effectivity of the immune response of the host. However, due … to the complexity of the immunologic cascade initiated during infection, the latter cannot be predicted easily. We construct a biomathematical model of the murine immune response during infection with pneumococcus aiming at predicting the outcome of antibiotic treatment. The model consists of a number of non-linear ordinary differential equations describing dynamics of pneumococcal population, the inflammatory cytokine IL-6, neutrophils and macrophages fighting the infection and destruction of alveolar tissue due to pneumococcus. Equations were derived by translating known biological mechanisms and assuming certain response kinetics. Antibiotic therapy is modelled by a transient depletion of bacteria. Unknown model parameters were determined by fitting the predictions of the model to data sets derived from mice experiments of pneumococcal lung infection with and without antibiotic treatment. Time series of pneumococcal population, debris, neutrophils, activated epithelial cells, macrophages, monocytes and IL-6 serum concentrations were available for this purpose. The antibiotics Ampicillin and Moxifloxacin were considered. Parameter fittings resulted in a good agreement of model and data for all experimental scenarios. Identifiability of parameters is also estimated. The model can be used to predict the performance of alternative schedules of antibiotic treatment. We conclude that we established a biomathematical model of pneumococcal lung infection in mice allowing predictions regarding the outcome of different schedules of antibiotic treatment. We aim at translating the model to the human situation in the near future.

Authors: Sibylle Schirm, Peter Ahnert, Sandra Wienhold, Holger Mueller-Redetzky, Geraldine Nouailles-Kursar, Markus Loeffler, Martin Witzenrath, Markus Scholz

Date Published: 19th May 2016

Publication Type: Journal article

Time to wake up: No impact of COMT Val158Met gene variation on circadian preferences, arousal regulation and sleep.
LIFE Adult, Genetical Statistics and Systems Biology

Abstract (Expand)

Dopamine has been implicated in the regulation of sleep-wake states and the circadian rhythm. However, there is no consensus on the impact of two established dopaminergic gene variants: the … catechol-O-methyltransferase Val158Met (COMT Val158Met; rs4680) and the dopamine D4 receptor Exon III variable-number-of-tandem-repeat polymorphism (DRD4 VNTR). Pursuing a multi-method approach, we examined their potential effects on circadian preferences, arousal regulation and sleep. Subjects underwent a 7-day actigraphy assessment (SenseWear Pro3), a 20-minute resting EEG (analyzed using VIGALL 2.0) and a body mass index (BMI) assessment. Further, they completed the Morningness-Eveningness Questionnaire (MEQ), the Epworth Sleepiness Scale (ESS) and the Pittsburgh Sleep Quality Index (PSQI). The sample comprised 4625 subjects (19-82 years) genotyped for COMT Val158Met, and 689 elderly subjects (64-82 years) genotyped for DRD4 VNTR. The number of subjects varied across phenotypes. Power calculations revealed a minimum required phenotypic variance explained by genotype ranging between 0.5% and 1.5% for COMT Val158Met and between 3.3% and 6.0% for DRD4 VNTR. Analyses did not reveal significant genotype effects on MEQ, ESS, PSQI, BMI, actigraphy and EEG variables. Additionally, we found no compelling evidence in sex- and age-stratified subsamples. Few associations surpassed the threshold of nominal significance (p < .05), providing some indication for a link between DRD4 VNTR and daytime sleepiness. Taken together, in light of the statistical power obtained in the present study, our data particularly suggest no impact of the COMT Val158Met polymorphism on circadian preferences, arousal regulation and sleep. The suggestive link between DRD4 VNTR and daytime sleepiness, on the other hand, might be worth investigation in a sample enriched with younger adults.

Authors: P. Jawinski, S. Tegelkamp, C. Sander, M. Hantzsch, J. Huang, N. Mauche, M. Scholz, J. Spada, C. Ulke, R. Burkhardt, A. Reif, U. Hegerl, T. Hensch

Date Published: 6th May 2016

Publication Type: Not specified

Reliability of 3D laser-based anthropometry and comparison with classical anthropometry
Genetical Statistics and Systems Biology

Abstract (Expand)

Anthropometric quantities are widely used in epidemiologic research as possible confounders, risk factors, or outcomes. 3D laser-based body scans (BS) allow evaluation of dozens of quantities in short … time with minimal physical contact between observers and probands. The aim of this study was to compare BS with classical manual anthropometric (CA) assessments with respect to feasibility, reliability, and validity. We performed a study on 108 individuals with multiple measurements of BS and CA to estimate intra- and inter-rater reliabilities for both. We suggested BS equivalents of CA measurements and determined validity of BS considering CA the gold standard. Throughout the study, the overall concordance correlation coefficient (OCCC) was chosen as indicator of agreement. BS was slightly more time consuming but better accepted than CA. For CA, OCCCs for intra- and inter-rater reliability were greater than 0.8 for all nine quantities studied. For BS, 9 of 154 quantities showed reliabilities below 0.7. BS proxies for CA measurements showed good agreement (minimum OCCC \textgreater 0.77) after offset correction. Thigh length showed higher reliability in BS while upper arm length showed higher reliability in CA. Except for these issues, reliabilities of CA measurements and their BS equivalents were comparable.

Authors: Andreas Kuehnapfel, Peter Ahnert, Markus Loeffler, Anja Broda, Markus Scholz

Date Published: 1st May 2016

Publication Type: Journal article

Genome-wide association analysis of actigraphic sleep phenotypes in the LIFE Adult Study.
LIFE Adult, Genetical Statistics and Systems Biology

Abstract (Expand)

The genetic basis of sleep is still poorly understood. Despite the moderate to high heritability of sleep-related phenotypes, known genetic variants explain only a small proportion of the phenotypical … variance. However, most previous studies were based solely upon self-report measures. The present study aimed to conduct the first genome-wide association (GWA) of actigraphic sleep phenotypes. The analyses included 956 middle- to older-aged subjects (40-79 years) from the LIFE Adult Study. The SenseWear Pro 3 Armband was used to collect 11 actigraphic parameters of night- and daytime sleep and three parameters of rest (lying down). The parameters comprised measures of sleep timing, quantity and quality. A total of 7 141 204 single nucleotide polymorphisms (SNPs) were analysed after imputation and quality control. We identified several variants below the significance threshold of P </= 5x 10(-8) (not corrected for analysis of multiple traits). The most significant was a hit near UFL1 associated with sleep efficiency on weekdays (P = 1.39 x 10(-8) ). Further SNPs were close to significance, including an association between sleep latency and a variant in CSNK2A1 (P = 8.20 x 10(-8) ), a gene known to be involved in the regulation of circadian rhythm. In summary, our GWAS identified novel candidate genes with biological plausibility being promising candidates for replication and further follow-up studies.

Authors: J. Spada, M. Scholz, H. Kirsten, T. Hensch, K. Horn, P. Jawinski, C. Ulke, R. Burkhardt, K. Wirkner, M. Loeffler, U. Hegerl, C. Sander

Date Published: 30th Apr 2016

Publication Type: Journal article

Relationship Between Determinants of Arterial Stiffness Assessed by Diastolic and Suprasystolic Pulse Oscillometry: Comparison of Vicorder and Vascular Explorer.
Genetical Statistics and Systems Biology, LIFE Heart

Abstract (Expand)

Pulse wave velocity (PWV) and augmentation index (AI) are independent predictors of cardiovascular health. However, the comparability of multiple oscillometric modalities currently available for their … assessment was not studied in detail. In the present study, we aimed to evaluate the relationship between indices of arterial stiffness assessed by diastolic and suprasystolic oscillometry.In total, 56 volunteers from the general population (23 males; median age 70 years [interquartile range: 65-72 years]) were recruited into observational feasibility study to evaluate the carotid-femoral/aortic PWV (cf/aoPWV), brachial-ankle PWV (baPWV), and AI assessed by 2 devices: Vicorder (VI) applying diastolic, right-sided oscillometry for the determination of all 3 indices, and Vascular explorer (VE) implementing single-point, suprasystolic brachial oscillometry (SSBO) pulse wave analysis for the assessment of cfPWV and AI. Within- and between-device correlations of measured parameters were analyzed. Furthermore, agreement of repeated measurements, intra- and inter-observer concordances were determined and compared for both devices.In VI, both baPWV and cfPWV inter-correlated well and showed good level of agreement with bilateral baPWV measured by VE (baPWV[VI]-baPWV[VE]R: overall concordance correlation coefficient [OCCC] = 0.484, mean difference = 1.94 m/s; cfPWV[VI]-baPWV[VE]R: OCCC = 0.493, mean difference = 1.0 m/s). In contrast, SSBO-derived aortic PWA (cf/aoPWA[VE]) displayed only weak correlation with cfPWV(VI) (r = 0.196; P = 0.04) and ipsilateral baPWV (cf/aoPWV[VE]R-baPWV[VE]R: r = 0.166; P = 0.08). cf/aoPWA(VE) correlated strongly with AI(VE) (right-sided: r = 0.725, P < 0.001). AI exhibited marginal between-device agreement (right-sided: OCCC = 0.298, mean difference: 6.12%). All considered parameters showed good-to-excellent repeatability giving OCCC > 0.9 for 2-point-PWV modes and right-sided AI(VE). Intra- and inter-observer concordances were similarly high except for AI yielding a trend toward better reproducibility in VE (interobserver-OCCC[VI] vs [VE] = 0.774 vs 0.844; intraobserver-OCCC[VI] vs [VE] = 0.613 vs 0.769).Both diastolic oscillometry-derived PWV modes, and AI measured either with VI or VE, are comparable and reliable alternatives for the assessment of arterial stiffness. Aortic PWV assessed by SSBO in VE is not related to the corresponding indices determined by traditional diastolic oscillometry.

Authors: A. Teren, F. Beutner, K. Wirkner, M. Loffler, M. Scholz

Date Published: 11th Mar 2016

Publication Type: Journal article

Prevalence of BRCA1/2 germline mutations in 21 401 families with breast and ovarian cancer.
GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Abstract (Expand)

PURPOSE: To characterise the prevalence of pathogenic germline mutations in BRCA1 and BRCA2 in families with breast cancer (BC) and ovarian cancer (OC) history. PATIENTS AND METHODS: Data from 21 401 … families were gathered between 1996 and 2014 in a clinical setting in the German Consortium for Hereditary Breast and Ovarian Cancer, comprising full pedigrees with cancer status of all individual members at the time of first counselling, and BRCA1/2 mutation status of the index patient. RESULTS: The overall BRCA1/2 mutation prevalence was 24.0% (95% CI 23.4% to 24.6%). Highest mutation frequencies were observed in families with at least two OCs (41.9%, 95% CI 36.1% to 48.0%) and families with at least one breast and one OC (41.6%, 95% CI 40.3% to 43.0%), followed by male BC with at least one female BC or OC (35.8%; 95% CI 32.2% to 39.6%). In families with a single case of early BC (<36 years), mutations were found in 13.7% (95% CI 11.9% to 15.7%). Postmenopausal unilateral or bilateral BC did not increase the probability of mutation detection. Occurrence of premenopausal BC and OC in the same woman led to higher mutation frequencies compared with the occurrence of these two cancers in different individuals (49.0%; 95% CI 41.0% to 57.0% vs 31.5%; 95% CI 28.0% to 35.2%). CONCLUSIONS: Our data provide guidance for healthcare professionals and decision-makers to identify individuals who should undergo genetic testing for hereditary breast and ovarian cancer. Moreover, it supports informed decision-making of counselees on the uptake of genetic testing.

Authors: K. Kast, K. Rhiem, B. Wappenschmidt, E. Hahnen, J. Hauke, B. Bluemcke, V. Zarghooni, N. Herold, N. Ditsch, M. Kiechle, M. Braun, C. Fischer, N. Dikow, S. Schott, N. Rahner, D. Niederacher, T. Fehm, A. Gehrig, C. Mueller-Reible, N. Arnold, N. Maass, G. Borck, N. de Gregorio, C. Scholz, B. Auber, R. Varon-Manteeva, D. Speiser, J. Horvath, N. Lichey, P. Wimberger, S. Stark, U. Faust, B. H. Weber, G. Emons, S. Zachariae, A. Meindl, R. K. Schmutzler, C. Engel

Date Published: 2nd Mar 2016

Publication Type: Journal article

Human Diseases: breast cancer, ovarian cancer

Modeling combined chemo- and immunotherapy of high-grade non-Hodgkin lymphoma.
LIFE - Leipzig Research Center for Civilization Diseases, Genetical Statistics and Systems Biology

Abstract (Expand)

Moderate, but not massive intensification of CHOP-21 improves outcome in aggressive non-Hodgkin lymphoma. Adding immunotherapy with Rituximab was a break-through, but levels differences in chemotherapy. … Ongoing trials attempt to optimize R-CHOP type regimens. We present a mathematical model of chemo-immunotherapy to explain published and aiming at predicting future trials comparing R-CHOP variants. We hypothesize that, for cure, the immune system must dominate residual tumor cells at the end of treatment. Chemotherapy reduces both tumor and immune cells. Rituximab immunotherapy boosts the immune response. We translate this reasoning into a differential equations model. Model parameters are estimated using data of randomized clinical trials in elderly patients. The model explains observed hazard ratios between treatments. It explains why too intense chemotherapy could be detrimental. The model is validated predicting six published independent studies. As an application, we varied treatment schedules and predict that current R-CHOP variants have only limited optimization potential.

Authors: K. Rosch, M. Scholz, D. Hasenclever

Date Published: 16th Dec 2015

Publication Type: Not specified

Human Diseases: lymphoma

The role of HPV RNA transcription, immune response-related gene expression and disruptive TP53 mutations in diagnostic and prognostic profiling of head and neck cancer.
LIFE HNC - Head and Neck Cancer Group, Genetical Statistics and Systems Biology

Abstract (Expand)

Stratification of head and neck squamous cell carcinomas (HNSCC) based on HPV16 DNA and RNA status, gene expression patterns, and mutated candidate genes may facilitate patient treatment decision. We … characterize head and neck squamous cell carcinomas (HNSCC) with different HPV16 DNA and RNA (E6*I) status from 290 consecutively recruited patients by gene expression profiling and targeted sequencing of 50 genes. We show that tumors with transcriptionally inactive HPV16 (DNA+ RNA-) are similar to HPV-negative (DNA-) tumors regarding gene expression and frequency of TP53 mutations (47%, 8/17 and 43%, 72/167, respectively). We also find that an immune response-related gene expression cluster is associated with lymph node metastasis, independent of HPV16 status and that disruptive TP53 mutations are associated with lymph node metastasis in HPV16 DNA- tumors. We validate each of these associations in another large data set. Four gene expression clusters which we identify differ moderately but significantly in overall survival. Our findings underscore the importance of measuring the HPV16 RNA (E6*I) and TP53-mutation status for patient stratification and identify associations of an immune response-related gene expression cluster and TP53 mutations with lymph node metastasis in HNSCC.

Authors: G. Wichmann, M. Rosolowski, K. Krohn, M. Kreuz, A. Boehm, A. Reiche, U. Scharrer, D. Halama, J. Bertolini, U. Bauer, D. Holzinger, M. Pawlita, J. Hess, C. Engel, D. Hasenclever, M. Scholz, P. Ahnert, H. Kirsten, A. Hemprich, C. Wittekind, O. Herbarth, F. Horn, A. Dietz, M. Loeffler

Date Published: 15th Dec 2015

Publication Type: Not specified

Human Diseases: head and neck cancer

Genetic variants of lipase activity in chronic pancreatitis
Genetical Statistics and Systems Biology

Abstract

Not specified

Authors: Holger Kirsten, Markus Scholz, Peter Kovacs, Harald Grallert, Annette Peters, Konstantin Strauch, Josef Frank, Marcella Rietschel, Markus M. Nöthen, Heiko Witt, Jonas Rosendahl

Date Published: 8th Dec 2015

Publication Type: Journal article

Independent Risk Factors for Fast-Track Failure Using a Predefined Fast-Track Protocol in Preselected Cardiac Surgery Patients
Genetical Statistics and Systems Biology

Abstract (Expand)

OBJECTISVES The purpose of this study was to identify the independent risk factors for fast-track failure (FTF) in cardiac surgery patients. DESIGN A retrospective analysis. SETTING A university-affiliated …iated heart center. PARTICIPANTS In a 2-year period, 1,704 consecutive preselected patients undergoing elective cardiac surgery were treated according to the local fast-track protocol in the postanesthetic care unit (PACU), bypassing the intensive care unit (ICU). MEASUREMENTS AND RESULTS Independent risk factors for FTF in the univariate regression analysis were tested in a multivariate regression analysis. FTF was defined as any transfer of the preselected patient to the ICU. FTF was primary when the patient was transferred directly from the postanesthetic care unit to the ICU and secondary when the patient was transferred from the intermediate care unit or ward to the ICU. FTF rate was 11.6% for primary and 5.6% for secondary FTF. In the multivariate regression analysis, age\textgreater70 years, female sex, prolonged surgery, and prolonged cross-clamp time could be defined as independent risk factors for FTF. CONCLUSIONS In a preselected patient population, fast-track treatment could be done with a low FTF rate. Independent risk factors for FTF are age, female sex, prolonged surgery, and prolonged cross-clamp time.

Authors: Zakhary Waseem, Jacob Lindner, Sophia Sgouropoulou, Sarah Eibel, Stefan Probst, Markus Scholz, Joerg Ender

Date Published: 1st Dec 2015

Publication Type: Journal article

Fibrinogen is not a prognostic factor for response to HELP-apheresis in sudden sensorineural hearing loss (SSHL)
Genetical Statistics and Systems Biology

Abstract (Expand)

Higher levels of fibrinogen or cholesterol were associated with improved hearing recovery in SSHL patients after treatment with HELP-apheresis (Heparin-induced extracorporeal LDL precipitation apheresis). … The present trial was performed to demonstrate HELP-related effects on relevant metabolic and inflammatory parameters in the context of SSHL treatment. In the framework of a single arm non-controlled trial, we investigated the variation of metabolic and inflammatory parameters using HELP-apheresis for a defined group of 100 patients with SSHL. Based on cut off inclusion criteria (Serum LDL-cholesterol >1.6 g/l and/or fibrinogen >2.0 g/l, SSHL in minimum three frequencies more than 30 dB, time after event not longer than 6 days), the protocol followed a strict time line with one single shot HELP-apheresis and follow-up monitoring including laboratory parameters at six defined time points. If HELP-apheresis could not effect improvement of hearing on day 5, additional corticosteroid treatment was applied. Concentration of anti-inflammatory IL-10 increased while other proinflammatory parameters declined. Serum levels of all measured sterols and apolipoproteins decreased significantly. None of the investigated parameters were suitable to predict hearing improvement of the patients. Levels of fibrinogen and LDL-cholesterol were not prognostic for outcome after HELP-apheresis. A significant (p < 0.001) increase of anti-inflammatory IL-10 after apheresis was notable, while most of the proinflammatory parameters declined. Despite the limited validity of a single arm non-controlled trial, these alterations on immune modulating factors indicate possible secondary pleiotropic effects caused by HELP-apheresis.

Authors: T. Berger, T. Kaiser, M. Scholz, A. Bachmann, U. Ceglarek, G. Hesse, B. Hagemeyer, M. Stumvoll, J. Thiery, A. Dietz

Date Published: 1st Dec 2015

Publication Type: Journal article

Brain Arousal Regulation in Carriers of Bipolar Disorder Risk Alleles.
LIFE Adult

Abstract (Expand)

OBJECTIVES: Recent genome-wide association studies identified a number of chromosomal risk loci for bipolar disorder (BD, 'manic-depressive illness'). According to the vigilance regulation … model, the regulation of brain arousal (referred to as 'vigilance') when assessed via EEG is an emerging biomarker linked to the pathogenesis of manic and depressive episodes. On this basis, the present study aimed to assess whether carriers of BD risk alleles differ in brain arousal regulation. METHODS: Healthy participants of the population-based Leipzig Health Care Study (LIFE) underwent a 20-min eyes-closed resting EEG paradigm. Brain arousal was assessed applying the computer-based Vigilance Algorithm Leipzig (VIGALL). The primary sample (n = 540) was genotyped for ten of the most reliable BD risk variants, of which two qualified for replication (n = 509). RESULTS: Primary sample analyses revealed Bonferroni-adjusted significance for rs1006737 in CACNA1C (encoding a calcium channel subunit), with risk allele carriers exhibiting relatively steep brain arousal declines. Further, carriers of two risk alleles of rs472913 at 1p32.1 showed generally lower brain arousal levels for the duration of the resting paradigm. However, both associations failed replication. CONCLUSION: Although our initial findings are in line with the vigilance regulation model and convincing in view of the previously reported notable role of ion channelopathies in BD, our results do not provide consistent evidence for a link between BD risk variants and brain arousal regulation. Several between-sample differences may account for this inconsistency. The molecular genetics of brain arousal regulation remain to be clarified.

Authors: P. Jawinski, C. Sander, N. Mauche, J. Spada, J. Huang, A. Schmidt, M. Hantzsch, R. Burkhardt, M. Scholz, U. Hegerl, T. Hensch

Date Published: 29th Oct 2015

Publication Type: Not specified

Human Diseases: bipolar disorder

Integration of Genome-Wide SNP Data and Gene-Expression Profiles Reveals Six Novel Loci and Regulatory Mechanisms for Amino Acids and Acylcarnitines in Whole Blood.
Genetical Statistics and Systems Biology

Abstract (Expand)

Profiling amino acids and acylcarnitines in whole blood spots is a powerful tool in the laboratory diagnosis of several inborn errors of metabolism. Emerging data suggests that altered blood levels of … amino acids and acylcarnitines are also associated with common metabolic diseases in adults. Thus, the identification of common genetic determinants for blood metabolites might shed light on pathways contributing to human physiology and common diseases. We applied a targeted mass-spectrometry-based method to analyze whole blood concentrations of 96 amino acids, acylcarnitines and pathway associated metabolite ratios in a Central European cohort of 2,107 adults and performed genome-wide association (GWA) to identify genetic modifiers of metabolite concentrations. We discovered and replicated six novel loci associated with blood levels of total acylcarnitine, arginine (both on chromosome 6; rs12210538, rs17657775), propionylcarnitine (chromosome 10; rs12779637), 2-hydroxyisovalerylcarnitine (chromosome 21; rs1571700), stearoylcarnitine (chromosome 1; rs3811444), and aspartic acid traits (chromosome 8; rs750472). Based on an integrative analysis of expression quantitative trait loci in blood mononuclear cells and correlations between gene expressions and metabolite levels, we provide evidence for putative causative genes: SLC22A16 for total acylcarnitines, ARG1 for arginine, HLCS for 2-hydroxyisovalerylcarnitine, JAM3 for stearoylcarnitine via a trans-effect at chromosome 1, and PPP1R16A for aspartic acid traits. Further, we report replication and provide additional functional evidence for ten loci that have previously been published for metabolites measured in plasma, serum or urine. In conclusion, our integrative analysis of SNP, gene-expression and metabolite data points to novel genetic factors that may be involved in the regulation of human metabolism. At several loci, we provide evidence for metabolite regulation via gene-expression and observed overlaps with GWAS loci for common diseases. These results form a strong rationale for subsequent functional and disease-related studies.

Authors: R. Burkhardt, H. Kirsten, F. Beutner, L. M. Holdt, A. Gross, A. Teren, A. Tonjes, S. Becker, K. Krohn, P. Kovacs, M. Stumvoll, D. Teupser, J. Thiery, U. Ceglarek, M. Scholz

Date Published: 25th Sep 2015

Publication Type: Not specified

Human Diseases: kidney disease

Genetic Contribution of Variants near SORT1 and APOE on LDL Cholesterol Independent of Obesity in Children
Genetical Statistics and Systems Biology

Abstract (Expand)

OBJECTIVE To assess potential effects of variants in six lipid modulating genes (SORT1, HMGCR, MLXIPL, FADS2, APOE and MAFB) on early development of dyslipidemia independent of the degree of obesity …y in children, we investigated their association with total (TC), low density lipoprotein (LDL-C), high density lipoprotein (HDL-C) cholesterol and triglyceride (TG) levels in 594 children. Furthermore, we evaluated the expression profile of the candidate genes during human adipocyte differentiation. RESULTS Expression of selected genes increased 101 to \textgreater104 fold during human adipocyte differentiation, suggesting a potential link with adipogenesis. In genetic association studies adjusted for age, BMI SDS and sex, we identified significant associations for rs599839 near SORT1 with TC and LDL-C and for rs4420638 near APOE with TC and LDL-C. We performed Bayesian modelling of the combined lipid phenotype of HDL-C, LDL-C and TG to identify potentially causal polygenic effects on this multi-dimensional phenotype and considering obesity, age and sex as a-priori modulating factors. This analysis confirmed that rs599839 and rs4420638 affect LDL-C. CONCLUSION We show that lipid modulating genes are dynamically regulated during adipogenesis and that variants near SORT1 and APOE influence lipid levels independent of obesity in children. Bayesian modelling suggests causal effects of these variants.   OBJECTIVE To assess potential effects of variants in six lipid modulating genes (SORT1, HMGCR, MLXIPL, FADS2, APOE and MAFB) on early development of dyslipidemia independent of the degree of obesity in children, we investigated their association with total (TC), low density lipoprotein (LDL-C), high density lipoprotein (HDL-C) cholesterol and triglyceride (TG) levels in 594 children. Furthermore, we evaluated the expression profile of the candidate genes during human adipocyte differentiation. RESULTS Expression of selected genes increased 10(1) to \textgreater10(4) fold during human adipocyte differentiation, suggesting a potential link with adipogenesis. In genetic association studies adjusted for age, BMI SDS and sex, we identified significant associations for rs599839 near SORT1 with TC and LDL-C and for rs4420638 near APOE with TC and LDL-C. We performed Bayesian modelling of the combined lipid phenotype of HDL-C, LDL-C and TG to identify potentially causal polygenic effects on this multi-dimensional phenotype and considering obesity, age and sex as a-priori modulating factors. This analysis confirmed that rs599839 and rs4420638 affect LDL-C. CONCLUSION We show that lipid modulating genes are dynamically regulated during adipogenesis and that variants near SORT1 and APOE influence lipid levels independent of obesity in children. Bayesian modelling suggests causal effects of these variants. //  OBJECTIVE To assess potential effects of variants in six lipid modulating genes (SORT1, HMGCR, MLXIPL, FADS2, APOE and MAFB) on early development of dyslipidemia independent of the degree of obesity in children, we investigated their association with total (TC), low density lipoprotein (LDL-C), high density lipoprotein (HDL-C) cholesterol and triglyceride (TG) levels in 594 children. Furthermore, we evaluated the expression profile of the candidate genes during human adipocyte differentiation. RESULTS Expression of selected genes increased 10(1) to \textgreater10(4) fold during human adipocyte differentiation, suggesting a potential link with adipogenesis. In genetic association studies adjusted for age, BMI SDS and sex, we identified significant associations for rs599839 near SORT1 with TC and LDL-C and for rs4420638 near APOE with TC and LDL-C. We performed Bayesian modelling of the combined lipid phenotype of HDL-C, LDL-C and TG to identify potentially causal polygenic effects on this multi-dimensional phenotype and considering obesity, age and sex as a-priori modulating factors. This analysis confirmed that rs599839 and rs4420638 affect LDL-C. CONCLUSION We show that lipid modulating genes are dynamically regulated during adipogenesis and that variants near SORT1 and APOE influence lipid levels independent of obesity in children. Bayesian modelling suggests causal effects of these variants.   OBJECTIVE To assess potential effects of variants in six lipid modulating genes (SORT1, HMGCR, MLXIPL, FADS2, APOE and MAFB) on early development of dyslipidemia independent of the degree of obesity in children, we investigated their association with total (TC), low density lipoprotein (LDL-C), high density lipoprotein (HDL-C) cholesterol and triglyceride (TG) levels in 594 children. Furthermore, we evaluated the expression profile of the candidate genes during human adipocyte differentiation. RESULTS Expression of selected genes increased 10(1) to \textgreater10(4) fold during human adipocyte differentiation, suggesting a potential link with adipogenesis. In genetic association studies adjusted for age, BMI SDS and sex, we identified significant associations for rs599839 near SORT1 with TC and LDL-C and for rs4420638 near APOE with TC and LDL-C. We performed Bayesian modelling of the combined lipid phenotype of HDL-C, LDL-C and TG to identify potentially causal polygenic effects on this multi-dimensional phenotype and considering obesity, age and sex as a-priori modulating factors. This analysis confirmed that rs599839 and rs4420638 affect LDL-C. CONCLUSION We show that lipid modulating genes are dynamically regulated during adipogenesis and that variants near SORT1 and APOE influence lipid levels independent of obesity in children. Bayesian modelling suggests causal effects of these variants. //  OBJECTIVE To assess potential effects of variants in six lipid modulating genes (SORT1, HMGCR, MLXIPL, FADS2, APOE and MAFB) on early development of dyslipidemia independent of the degree of obesity in children, we investigated their association with total (TC), low density lipoprotein (LDL-C), high density lipoprotein (HDL-C) cholesterol and triglyceride (TG) levels in 594 children. Furthermore, we evaluated the expression profile of the candidate genes during human adipocyte differentiation. RESULTS Expression of selected genes increased 10(1) to \textgreater10(4) fold during human adipocyte differentiation, suggesting a potential link with adipogenesis. In genetic association studies adjusted for age, BMI SDS and sex, we identified significant associations for rs599839 near SORT1 with TC and LDL-C and for rs4420638 near APOE with TC and LDL-C. We performed Bayesian modelling of the combined lipid phenotype of HDL-C, LDL-C and TG to identify potentially causal polygenic effects on this multi-dimensional phenotype and considering obesity, age and sex as a-priori modulating factors. This analysis confirmed that rs599839 and rs4420638 affect LDL-C. CONCLUSION We show that lipid modulating genes are dynamically regulated during adipogenesis and that variants near SORT1 and APOE influence lipid levels independent of obesity in children. Bayesian modelling suggests causal effects of these variants.

Authors: Clara Breitling, Arnd Gross, Petra Büttner, Sebastian Weise, Dorit Schleinitz, Wieland Kiess, Markus Scholz, Peter Kovacs, Antje Körner

Date Published: 16th Sep 2015

Publication Type: Journal article

The value of noncoronary atherosclerosis for identifying coronary artery disease: results of the Leipzig LIFE Heart Study.
Genetical Statistics and Systems Biology, LIFE Heart

Abstract (Expand)

BACKGROUND: Despite the widespread use of noninvasive testing prior to invasive coronary diagnostic the diagnostic yield of elective coronary angiography has been reported low in subjects with suspected … obstructive CAD. OBJECTIVE: To determine the predictive value of noncoronary atherosclerosis (NCA) in subjects with suspected stable coronary artery disease (CAD) intended to invasive coronary angiography. METHODS: Ultrasound-based assessment of carotid artery plaque (CAP), carotid intima-media thickness (CIMT) and ankle-brachial index (ABI) was performed in 2216 subjects with suspected CAD prior to coronary angiography. Logistic regression and c-statistics were used to analyze the diagnostic value of NCA for the presence of obstructive CAD and the intention to revascularization. RESULTS: Percentage of positive results of elective coronary angiography was low but comparable to other studies (41% obstructive CAD). We identified 1323 subjects (60%) with NCA, most of them were characterized by CAP (93%). CAP independently predicted obstructive CAD in addition to traditional risk factors and clinical factors while CIMT and ABI failed to improve the prediction. The presence of NCA and typical angina were the strongest predictors for obstructive CAD (OR 4.0 and 2.4, respectively). A large subgroup of patients (n = 703, 32%) with atypical clinical presentation and lack of NCA revealed a low indication for revascularization <15% indicating a large proportion of subjects with non-obstructive CAD in this subgroup. CONCLUSION: The evaluation of noncoronary atherosclerosis has the potential to impact clinical decision making and to direct subsequent diagnostic procedures in subjects with suspected coronary artery disease. CLINICAL TRIAL REGISTRATION: NCT00497887.

Authors: A. Weissgerber, M. Scholz, A. Teren, M. Sandri, D. Teupser, S. Gielen, J. Thiery, G. Schuler, F. Beutner

Date Published: 13th Sep 2015

Publication Type: Not specified

Human Diseases: coronary artery disease, atherosclerosis

Dissecting the genetics of the human transcriptome identifies novel trait-related trans-eQTLs and corroborates the regulatory relevance of non-protein coding locidagger.
Genetical Statistics and Systems Biology, LIFE Heart

Abstract (Expand)

Genetics of gene expression (eQTLs or expression QTLs) has proved an indispensable tool for understanding biological pathways and pathomechanisms of trait-associated SNPs. However, power of most … genome-wide eQTL studies is still limited. We performed a large eQTL study in peripheral blood mononuclear cells of 2112 individuals increasing the power to detect trans-effects genome-wide. Going beyond univariate SNP-transcript associations, we analyse relations of eQTLs to biological pathways, polygenetic effects of expression regulation, trans-clusters and enrichment of co-localized functional elements. We found eQTLs for about 85% of analysed genes, and 18% of genes were trans-regulated. Local eSNPs were enriched up to a distance of 5 Mb to the transcript challenging typically implemented ranges of cis-regulations. Pathway enrichment within regulated genes of GWAS-related eSNPs supported functional relevance of identified eQTLs. We demonstrate that nearest genes of GWAS-SNPs might frequently be misleading functional candidates. We identified novel trans-clusters of potential functional relevance for GWAS-SNPs of several phenotypes including obesity-related traits, HDL-cholesterol levels and haematological phenotypes. We used chromatin immunoprecipitation data for demonstrating biological effects. Yet, we show for strongly heritable transcripts that still little trans-chromosomal heritability is explained by all identified trans-eSNPs; however, our data suggest that most cis-heritability of these transcripts seems explained. Dissection of co-localized functional elements indicated a prominent role of SNPs in loci of pseudogenes and non-coding RNAs for the regulation of coding genes. In summary, our study substantially increases the catalogue of human eQTLs and improves our understanding of the complex genetic regulation of gene expression, pathways and disease-related processes.

Authors: H. Kirsten, H. Al-Hasani, L. Holdt, A. Gross, F. Beutner, K. Krohn, K. Horn, P. Ahnert, R. Burkhardt, K. Reiche, J. Hackermuller, M. Loffler, D. Teupser, J. Thiery, M. Scholz

Date Published: 15th Aug 2015

Publication Type: Journal article

Lineage-Specific Changes in Biomarkers in Great Apes and Humans
Genetical Statistics and Systems Biology

Abstract (Expand)

Although human biomedical and physiological information is readily available, such information for great apes is limited. We analyzed clinical chemical biomarkers in serum samples from 277 wild- and … captive-born great apes and from 312 healthy human volunteers as well as from 20 rhesus macaques. For each individual, we determined a maximum of 33 markers of heart, liver, kidney, thyroid and pancreas function, hemoglobin and lipid metabolism and one marker of inflammation. We identified biomarkers that show differences between humans and the great apes in their average level or activity. Using the rhesus macaques as an outgroup, we identified human-specific differences in the levels of bilirubin, cholinesterase and lactate dehydrogenase, and bonobo-specific differences in the level of apolipoprotein A-I. For the remaining twenty-nine biomarkers there was no evidence for lineage-specific differences. In fact, we find that many biomarkers show differences between individuals of the same species in different environments. Of the four lineage-specific biomarkers, only bilirubin showed no differences between wild- and captive-born great apes. We show that the major factor explaining the human-specific difference in bilirubin levels may be genetic. There are human-specific changes in the sequence of the promoter and the protein-coding sequence of uridine diphosphoglucuronosyltransferase 1 (UGT1A1), the enzyme that transforms bilirubin and toxic plant compounds into water-soluble, excretable metabolites. Experimental evidence that UGT1A1 is down-regulated in the human liver suggests that changes in the promoter may be responsible for the human-specific increase in bilirubin. We speculate that since cooking reduces toxic plant compounds, consumption of cooked foods, which is specific to humans, may have resulted in relaxed constraint on UGT1A1 which has in turn led to higher serum levels of bilirubin in humans.   Although human biomedical and physiological information is readily available, such information for great apes is limited. We analyzed clinical chemical biomarkers in serum samples from 277 wild- and captive-born great apes and from 312 healthy human volunteers as well as from 20 rhesus macaques. For each individual, we determined a maximum of 33 markers of heart, liver, kidney, thyroid and pancreas function, hemoglobin and lipid metabolism and one marker of inflammation. We identified biomarkers that show differences between humans and the great apes in their average level or activity. Using the rhesus macaques as an outgroup, we identified human-specific differences in the levels of bilirubin, cholinesterase and lactate dehydrogenase, and bonobo-specific differences in the level of apolipoprotein A-I. For the remaining twenty-nine biomarkers there was no evidence for lineage-specific differences. In fact, we find that many biomarkers show differences between individuals of the same species in different environments. Of the four lineage-specific biomarkers, only bilirubin showed no differences between wild- and captive-born great apes. We show that the major factor explaining the human-specific difference in bilirubin levels may be genetic. There are human-specific changes in the sequence of the promoter and the protein-coding sequence of uridine diphosphoglucuronosyltransferase 1 (UGT1A1), the enzyme that transforms bilirubin and toxic plant compounds into water-soluble, excretable metabolites. Experimental evidence that UGT1A1 is down-regulated in the human liver suggests that changes in the promoter may be responsible for the human-specific increase in bilirubin. We speculate that since cooking reduces toxic plant compounds, consumption of cooked foods, which is specific to humans, may have resulted in relaxed constraint on UGT1A1 which has in turn led to higher serum levels of bilirubin in humans. //  Although human biomedical and physiological information is readily available, such information for great apes is limited. We analyzed clinical chemical biomarkers in serum samples from 277 wild- and captive-born great apes and from 312 healthy human volunteers as well as from 20 rhesus macaques. For each individual, we determined a maximum of 33 markers of heart, liver, kidney, thyroid and pancreas function, hemoglobin and lipid metabolism and one marker of inflammation. We identified biomarkers that show differences between humans and the great apes in their average level or activity. Using the rhesus macaques as an outgroup, we identified human-specific differences in the levels of bilirubin, cholinesterase and lactate dehydrogenase, and bonobo-specific differences in the level of apolipoprotein A-I. For the remaining twenty-nine biomarkers there was no evidence for lineage-specific differences. In fact, we find that many biomarkers show differences between individuals of the same species in different environments. Of the four lineage-specific biomarkers, only bilirubin showed no differences between wild- and captive-born great apes. We show that the major factor explaining the human-specific difference in bilirubin levels may be genetic. There are human-specific changes in the sequence of the promoter and the protein-coding sequence of uridine diphosphoglucuronosyltransferase 1 (UGT1A1), the enzyme that transforms bilirubin and toxic plant compounds into water-soluble, excretable metabolites. Experimental evidence that UGT1A1 is down-regulated in the human liver suggests that changes in the promoter may be responsible for the human-specific increase in bilirubin. We speculate that since cooking reduces toxic plant compounds, consumption of cooked foods, which is specific to humans, may have resulted in relaxed constraint on UGT1A1 which has in turn led to higher serum levels of bilirubin in humans.

Authors: Claudius Ronke, Michael Dannemann, Michel Halbwax, Anne Fischer, Christin Helmschrodt, Mathias Brügel, Claudine André, Rebeca Atencia, Lawrence Mugisha, Markus Scholz, Uta Ceglarek, Joachim Thiery, Svante Pääbo, Kay Prüfer, Janet Kelso

Date Published: 6th Aug 2015

Publication Type: Journal article

The LIFE-Adult-Study: objectives and design of a population-based cohort study with 10,000 deeply phenotyped adults in Germany.
LIFE Adult, Genetical Statistics and Systems Biology

Abstract (Expand)

BACKGROUND: The LIFE-Adult-Study is a population-based cohort study, which has recently completed the baseline examination of 10,000 randomly selected participants from Leipzig, a major city with 550,000 … inhabitants in the east of Germany. It is the first study of this kind and size in an urban population in the eastern part of Germany. The study is conducted by the Leipzig Research Centre for Civilization Diseases (LIFE). Our objective is to investigate prevalences, early onset markers, genetic predispositions, and the role of lifestyle factors of major civilization diseases, with primary focus on metabolic and vascular diseases, heart function, cognitive impairment, brain function, depression, sleep disorders and vigilance dysregulation, retinal and optic nerve degeneration, and allergies. METHODS/DESIGN: The study covers a main age range from 40-79 years with particular deep phenotyping in elderly participants above the age of 60. The baseline examination was conducted from August 2011 to November 2014. All participants underwent an extensive core assessment programme (5-6 h) including structured interviews, questionnaires, physical examinations, and biospecimen collection. Participants over 60 underwent two additional assessment programmes (3-4 h each) on two separate visits including deeper cognitive testing, brain magnetic resonance imaging, diagnostic interviews for depression, and electroencephalography. DISCUSSION: The participation rate was 33 %. The assessment programme was accepted well and completely passed by almost all participants. Biomarker analyses have already been performed in all participants. Genotype, transcriptome and metabolome analyses have been conducted in subgroups. The first follow-up examination will commence in 2016.

Authors: M. Loeffler, C. Engel, P. Ahnert, D. Alfermann, K. Arelin, R. Baber, F. Beutner, H. Binder, E. Brahler, R. Burkhardt, U. Ceglarek, C. Enzenbach, M. Fuchs, H. Glaesmer, F. Girlich, A. Hagendorff, M. Hantzsch, U. Hegerl, S. Henger, T. Hensch, A. Hinz, V. Holzendorf, D. Husser, A. Kersting, A. Kiel, T. Kirsten, J. Kratzsch, K. Krohn, T. Luck, S. Melzer, J. Netto, M. Nuchter, M. Raschpichler, F. G. Rauscher, S. G. Riedel-Heller, C. Sander, M. Scholz, P. Schonknecht, M. L. Schroeter, J. C. Simon, R. Speer, J. Staker, R. Stein, Y. Stobel-Richter, M. Stumvoll, A. Tarnok, A. Teren, D. Teupser, F. S. Then, A. Tonjes, R. Treudler, A. Villringer, A. Weissgerber, P. Wiedemann, S. Zachariae, K. Wirkner, J. Thiery

Date Published: 22nd Jul 2015

Publication Type: Not specified

Human Diseases: disease of mental health, mental depression, vascular disease, allergic hypersensitivity disease, sleep disorder, retinal degeneration

Impact of genetic similarity on imputation accuracy.
LIFE - Leipzig Research Center for Civilization Diseases, Genetical Statistics and Systems Biology

Abstract (Expand)

BACKGROUND: Genotype imputation is a common technique in genetic research. Genetic similarity between target population and reference dataset is crucial for high-quality results. Although several … reference panels are available, it is often not clear which is the most optimal for a particular target dataset to be imputed. Maximizing genetic similarity between study sample and intended reference panels may be the straight forward method for selecting the genetically best-matched reference. However, the impact of genetic similarity on imputation accuracy has not yet been studied in detail. RESULTS: We performed a simulation study in 20 ethnic groups obtained from POPRES. High-quality SNPs were masked and re-imputed with MaCH, MaCH-minimac and IMPUTE2 using four different HapMap reference panels (CEU, CHB-JPT, MEX and YRI). Imputation accuracy was assessed by different statistics. Genetic similarity between ethnic groups and reference populations were measured by F -statistics (F(ST)) originally proposed by Wright and G -statistics (G(ST)) introduced by Nei and others. To assess the predictive power of these measures regarding imputation accuracy, we analysed relations between them and corresponding imputation accuracy scores. We found that population genetic distances between homogeneous reference and target populations were strongly linearly correlated with resulting imputation accuracies irrespective of considered distance measure, imputation accuracy measure, missingness and imputation software used. Possible exception was African population. CONCLUSION: Usage of G(ST) or F(ST)-related measures for predicting the optimal reference panel for imputation frameworks relying on a specific reference is highly recommended. A cut-off of G(ST) < 0.01 is recommended to achieve good imputation results for high-frequency variants and small data sets. The linear relationship is less pronounced for low-frequency variants for which we also observed a dependence of imputation accuracy on the number of polymorphic sites in the reference. We also show that the software specific measures MaCH-Rsq and IMPUTE-info must be interpreted with caution if the genetic distance of target and reference population is high.

Authors: N. R. Roshyara, M. Scholz

Date Published: 22nd Jul 2015

Publication Type: Not specified

Associations between DNA methylation and schizophrenia-related intermediate phenotypes - a gene set enrichment analysis
Genetical Statistics and Systems Biology

Abstract (Expand)

Multiple genetic approaches have identified microRNAs as key effectors in psychiatric disorders as they post-transcriptionally regulate expression of thousands of target genes. However, their role in … specific psychiatric diseases remains poorly understood. In addition, epigenetic mechanisms such as DNA methylation, which affect the expression of both microRNAs and coding genes, are critical for our understanding of molecular mechanisms in schizophrenia. Using clinical, imaging, genetic, and epigenetic data of 103 patients with schizophrenia and 111 healthy controls of the Mind Clinical Imaging Consortium (MCIC) study of schizophrenia, we conducted gene set enrichment analysis to identify markers for schizophrenia-associated intermediate phenotypes. Genes were ranked based on the correlation between DNA methylation patterns and each phenotype, and then searched for enrichment in 221 predicted microRNA target gene sets. We found the predicted hsa-miR-219a-5p target gene set to be significantly enriched for genes (EPHA4, PKNOX1, ESR1, among others) whose methylation status is correlated with hippocampal volume independent of disease status. Our results were strengthened by significant associations between hsa-miR-219a-5p target gene methylation patterns and hippocampus-related neuropsychological variables. IPA pathway analysis of the respective predicted hsa-miR-219a-5p target genes revealed associated network functions in behavior and developmental disorders. Altered methylation patterns of predicted hsa-miR-219a-5p target genes are associated with a structural aberration of the brain that has been proposed as a possible biomarker for schizophrenia. The (dys)regulation of microRNA target genes by epigenetic mechanisms may confer additional risk for developing psychiatric symptoms. Further study is needed to understand possible interactions between microRNAs and epigenetic changes and their impact on risk for brain-based disorders such as schizophrenia.   Multiple genetic approaches have identified microRNAs as key effectors in psychiatric disorders as they post-transcriptionally regulate expression of thousands of target genes. However, their role in specific psychiatric diseases remains poorly understood. In addition, epigenetic mechanisms such as DNA methylation, which affect the expression of both microRNAs and coding genes, are critical for our understanding of molecular mechanisms in schizophrenia. Using clinical, imaging, genetic, and epigenetic data of 103 patients with schizophrenia and 111 healthy controls of the Mind Clinical Imaging Consortium (MCIC) study of schizophrenia, we conducted gene set enrichment analysis to identify markers for schizophrenia-associated intermediate phenotypes. Genes were ranked based on the correlation between DNA methylation patterns and each phenotype, and then searched for enrichment in 221 predicted microRNA target gene sets. We found the predicted hsa-miR-219a-5p target gene set to be significantly enriched for genes (EPHA4, PKNOX1, ESR1, among others) whose methylation status is correlated with hippocampal volume independent of disease status. Our results were strengthened by significant associations between hsa-miR-219a-5p target gene methylation patterns and hippocampus-related neuropsychological variables. IPA pathway analysis of the respective predicted hsa-miR-219a-5p target genes revealed associated network functions in behavior and developmental disorders. Altered methylation patterns of predicted hsa-miR-219a-5p target genes are associated with a structural aberration of the brain that has been proposed as a possible biomarker for schizophrenia. The (dys)regulation of microRNA target genes by epigenetic mechanisms may confer additional risk for developing psychiatric symptoms. Further study is needed to understand possible interactions between microRNAs and epigenetic changes and their impact on risk for brain-based disorders such as schizophrenia.   Multiple genetic approaches have identified microRNAs as key effectors in psychiatric disorders as they post-transcriptionally regulate expression of thousands of target genes. However, their role in specific psychiatric diseases remains poorly understood. In addition, epigenetic mechanisms such as DNA methylation, which affect the expression of both microRNAs and coding genes, are critical for our understanding of molecular mechanisms in schizophrenia. Using clinical, imaging, genetic, and epigenetic data of 103 patients with schizophrenia and 111 healthy controls of the Mind Clinical Imaging Consortium (MCIC) study of schizophrenia, we conducted gene set enrichment analysis to identify markers for schizophrenia-associated intermediate phenotypes. Genes were ranked based on the correlation between DNA methylation patterns and each phenotype, and then searched for enrichment in 221 predicted microRNA target gene sets. We found the predicted hsa-miR-219a-5p target gene set to be significantly enriched for genes (EPHA4, PKNOX1, ESR1, among others) whose methylation status is correlated with hippocampal volume independent of disease status. Our results were strengthened by significant associations between hsa-miR-219a-5p target gene methylation patterns and hippocampus-related neuropsychological variables. IPA pathway analysis of the respective predicted hsa-miR-219a-5p target genes revealed associated network functions in behavior and developmental disorders. Altered methylation patterns of predicted hsa-miR-219a-5p target genes are associated with a structural aberration of the brain that has been proposed as a possible biomarker for schizophrenia. The (dys)regulation of microRNA target genes by epigenetic mechanisms may confer additional risk for developing psychiatric symptoms. Further study is needed to understand possible interactions between microRNAs and epigenetic changes and their impact on risk for brain-based disorders such as schizophrenia. //  Multiple genetic approaches have identified microRNAs as key effectors in psychiatric disorders as they post-transcriptionally regulate expression of thousands of target genes. However, their role in specific psychiatric diseases remains poorly understood. In addition, epigenetic mechanisms such as DNA methylation, which affect the expression of both microRNAs and coding genes, are critical for our understanding of molecular mechanisms in schizophrenia. Using clinical, imaging, genetic, and epigenetic data of 103 patients with schizophrenia and 111 healthy controls of the Mind Clinical Imaging Consortium (MCIC) study of schizophrenia, we conducted gene set enrichment analysis to identify markers for schizophrenia-associated intermediate phenotypes. Genes were ranked based on the correlation between DNA methylation patterns and each phenotype, and then searched for enrichment in 221 predicted microRNA target gene sets. We found the predicted hsa-miR-219a-5p target gene set to be significantly enriched for genes (EPHA4, PKNOX1, ESR1, among others) whose methylation status is correlated with hippocampal volume independent of disease status. Our results were strengthened by significant associations between hsa-miR-219a-5p target gene methylation patterns and hippocampus-related neuropsychological variables. IPA pathway analysis of the respective predicted hsa-miR-219a-5p target genes revealed associated network functions in behavior and developmental disorders. Altered methylation patterns of predicted hsa-miR-219a-5p target genes are associated with a structural aberration of the brain that has been proposed as a possible biomarker for schizophrenia. The (dys)regulation of microRNA target genes by epigenetic mechanisms may confer additional risk for developing psychiatric symptoms. Further study is needed to understand possible interactions between microRNAs and epigenetic changes and their impact on risk for brain-based disorders such as schizophrenia.

Authors: Johanna Hass, Esther Walton, Carrie Wright, Andreas Beyer, Markus Scholz, Jessica Turner, Jingyu Liu, Michael N. Smolka, Veit Roessner, Scott R. Sponheim, Randy L. Gollub, Vince D. Calhoun, Stefan Ehrlich

Date Published: 1st Jun 2015

Publication Type: Journal article

A recombined allele of the lipase gene CEL and its pseudogene CELP confers susceptibility to chronic pancreatitis
Genetical Statistics and Systems Biology

Abstract (Expand)

Carboxyl ester lipase is a digestive pancreatic enzyme encoded by the CEL gene. Mutations in CEL cause maturity-onset diabetes of the young as well as pancreatic exocrine dysfunction. Here we describe … a hybrid allele (CEL-HYB) originating from a crossover between CEL and its neighboring pseudogene, CELP. In a discovery series of familial chronic pancreatitis cases, we observed CEL-HYB in 14.1% (10/71) of cases compared to 1.0% (5/478) of controls (odds ratio (OR) = 15.5; 95% confidence interval (CI) = 5.1-46.9; P = 1.3 \times 10(-6) by two-tailed Fisher’s exact test). In three replication studies of nonalcoholic chronic pancreatitis, we identified CEL-HYB in a total of 3.7% (42/1,122) cases and 0.7% (30/4,152) controls (OR = 5.2; 95% CI = 3.2-8.5; P = 1.2 \times 10(-11); formal meta-analysis). The allele was also enriched in alcoholic chronic pancreatitis. Expression of CEL-HYB in cellular models showed reduced lipolytic activity, impaired secretion, prominent intracellular accumulation and induced autophagy. These findings implicate a new pathway distinct from the protease-antiprotease system of pancreatic acinar cells in chronic pancreatitis.   Carboxyl ester lipase is a digestive pancreatic enzyme encoded by the CEL gene. Mutations in CEL cause maturity-onset diabetes of the young as well as pancreatic exocrine dysfunction. Here we describe a hybrid allele (CEL-HYB) originating from a crossover between CEL and its neighboring pseudogene, CELP. In a discovery series of familial chronic pancreatitis cases, we observed CEL-HYB in 14.1% (10/71) of cases compared to 1.0% (5/478) of controls (odds ratio (OR) = 15.5; 95% confidence interval (CI) = 5.1-46.9; P = 1.3 \times 10(-6) by two-tailed Fisher’s exact test). In three replication studies of nonalcoholic chronic pancreatitis, we identified CEL-HYB in a total of 3.7% (42/1,122) cases and 0.7% (30/4,152) controls (OR = 5.2; 95% CI = 3.2-8.5; P = 1.2 \times 10(-11); formal meta-analysis). The allele was also enriched in alcoholic chronic pancreatitis. Expression of CEL-HYB in cellular models showed reduced lipolytic activity, impaired secretion, prominent intracellular accumulation and induced autophagy. These findings implicate a new pathway distinct from the protease-antiprotease system of pancreatic acinar cells in chronic pancreatitis.   Carboxyl ester lipase is a digestive pancreatic enzyme encoded by the CEL gene. Mutations in CEL cause maturity-onset diabetes of the young as well as pancreatic exocrine dysfunction. Here we describe a hybrid allele (CEL-HYB) originating from a crossover between CEL and its neighboring pseudogene, CELP. In a discovery series of familial chronic pancreatitis cases, we observed CEL-HYB in 14.1% (10/71) of cases compared to 1.0% (5/478) of controls (odds ratio (OR) = 15.5; 95% confidence interval (CI) = 5.1-46.9; P = 1.3 \times 10(-6) by two-tailed Fisher’s exact test). In three replication studies of nonalcoholic chronic pancreatitis, we identified CEL-HYB in a total of 3.7% (42/1,122) cases and 0.7% (30/4,152) controls (OR = 5.2; 95% CI = 3.2-8.5; P = 1.2 \times 10(-11); formal meta-analysis). The allele was also enriched in alcoholic chronic pancreatitis. Expression of CEL-HYB in cellular models showed reduced lipolytic activity, impaired secretion, prominent intracellular accumulation and induced autophagy. These findings implicate a new pathway distinct from the protease-antiprotease system of pancreatic acinar cells in chronic pancreatitis.   Carboxyl ester lipase is a digestive pancreatic enzyme encoded by the CEL gene. Mutations in CEL cause maturity-onset diabetes of the young as well as pancreatic exocrine dysfunction. Here we describe a hybrid allele (CEL-HYB) originating from a crossover between CEL and its neighboring pseudogene, CELP. In a discovery series of familial chronic pancreatitis cases, we observed CEL-HYB in 14.1% (10/71) of cases compared to 1.0% (5/478) of controls (odds ratio (OR) = 15.5; 95% confidence interval (CI) = 5.1-46.9; P = 1.3 \times 10(-6) by two-tailed Fisher’s exact test). In three replication studies of nonalcoholic chronic pancreatitis, we identified CEL-HYB in a total of 3.7% (42/1,122) cases and 0.7% (30/4,152) controls (OR = 5.2; 95% CI = 3.2-8.5; P = 1.2 \times 10(-11); formal meta-analysis). The allele was also enriched in alcoholic chronic pancreatitis. Expression of CEL-HYB in cellular models showed reduced lipolytic activity, impaired secretion, prominent intracellular accumulation and induced autophagy. These findings implicate a new pathway distinct from the protease-antiprotease system of pancreatic acinar cells in chronic pancreatitis. //  Carboxyl ester lipase is a digestive pancreatic enzyme encoded by the CEL gene. Mutations in CEL cause maturity-onset diabetes of the young as well as pancreatic exocrine dysfunction. Here we describe a hybrid allele (CEL-HYB) originating from a crossover between CEL and its neighboring pseudogene, CELP. In a discovery series of familial chronic pancreatitis cases, we observed CEL-HYB in 14.1% (10/71) of cases compared to 1.0% (5/478) of controls (odds ratio (OR) = 15.5; 95% confidence interval (CI) = 5.1-46.9; P = 1.3 \times 10(-6) by two-tailed Fisher’s exact test). In three replication studies of nonalcoholic chronic pancreatitis, we identified CEL-HYB in a total of 3.7% (42/1,122) cases and 0.7% (30/4,152) controls (OR = 5.2; 95% CI = 3.2-8.5; P = 1.2 \times 10(-11); formal meta-analysis). The allele was also enriched in alcoholic chronic pancreatitis. Expression of CEL-HYB in cellular models showed reduced lipolytic activity, impaired secretion, prominent intracellular accumulation and induced autophagy. These findings implicate a new pathway distinct from the protease-antiprotease system of pancreatic acinar cells in chronic pancreatitis.

Authors: Karianne Fjeld, Frank Ulrich Weiss, Denise Lasher, Jonas Rosendahl, Jian-Min Chen, Bente B. Johansson, Holger Kirsten, Claudia Ruffert, Emmanuelle Masson, Solrun J. Steine, Peter Bugert, Miriam Cnop, Robert Grützmann, Julia Mayerle, Joachim Mössner, Monika Ringdal, Hans-Ulrich Schulz, Matthias Sendler, Peter Simon, Paweł Sztromwasser, Janniche Torsvik, Markus Scholz, Erling Tjora, Claude Férec, Heiko Witt, Markus M. Lerch, Pål R. Njølstad, Stefan Johansson, Anders Molven

Date Published: 1st May 2015

Publication Type: Journal article

Common genomic variation in the FER gene: useful to stratify patients with sepsis due to pneumonia?
LIFE - Leipzig Research Center for Civilization Diseases

Abstract

Not specified

Authors: F. Schoneweck, E. Kuhnt, M. Scholz, F. M. Brunkhorst, A. Scherag

Date Published: 30th Apr 2015

Publication Type: Not specified

Human Diseases: bacterial infectious disease, pneumonia

Low-Dose Irradiation Affects Expression of Inflammatory Markers in the Heart of ApoE -/- Mice
Genetical Statistics and Systems Biology

Abstract (Expand)

Epidemiological studies indicate long-term risks of ionizing radiation on the heart, even at moderate doses. In this study, we investigated the inflammatory, thrombotic and fibrotic late responses of … the heart after low-dose irradiation (IR) with specific emphasize on the dose rate. Hypercholesterolemic ApoE-deficient mice were sacrificed 3 and 6 months after total body irradiation (TBI) with 0.025, 0.05, 0.1, 0.5 or 2 Gy at low (1 mGy/min) or high dose rate (150 mGy/min). The expression of inflammatory and thrombotic markers was quantified in frozen heart sections (CD31, E-selectin, thrombomodulin, ICAM-1, VCAM-1, collagen IV, Thy-1, and CD45) and in plasma samples (IL6, KC, MCP-1, TNF\textgreeka, INF\textgreekg, IL-1\textgreekb, TGF\textgreekb, INF\textgreekg, IL-10, sICAM-1, sE-selectin, sVCAM-1 and fibrinogen) by fluorescence analysis and ELISA. We found that even very low irradiation doses induced adaptive late responses, such as increases of capillary density and changes in collagen IV and Thy-1 levels indicating compensatory regulation. Slight decreases of ICAM-1 levels and reduction of Thy 1 expression at 0.025-0.5 Gy indicate anti-inflammatory effects, whereas at the highest dose (2 Gy) increased VCAM-1 levels on the endocardium may represent a switch to a pro-inflammatory response. Plasma samples partially confirmed this pattern, showing a decrease of proinflammatory markers (sVCAM, sICAM) at 0.025-2.0 Gy. In contrast, an enhancement of MCP-1, TNF\textgreeka and fibrinogen at 0.05-2.0 Gy indicated a proinflammatory and prothrombotic systemic response. Multivariate analysis also revealed significant age-dependent increases (KC, MCP-1, fibrinogen) and decreases (sICAM, sVCAM, sE-selectin) of plasma markers. This paper represents local and systemic effects of low-dose irradiation, including also age- and dose rate-dependent responses in the ApoE-/- mouse model. These insights in the multiple inflammatory/thrombotic effects caused by low-dose irradiation might facilitate an individual evaluation and intervention of radiation related, long-term side effects but also give important implications for low dose anti-inflammatory radiotherapy.   Epidemiological studies indicate long-term risks of ionizing radiation on the heart, even at moderate doses. In this study, we investigated the inflammatory, thrombotic and fibrotic late responses of the heart after low-dose irradiation (IR) with specific emphasize on the dose rate. Hypercholesterolemic ApoE-deficient mice were sacrificed 3 and 6 months after total body irradiation (TBI) with 0.025, 0.05, 0.1, 0.5 or 2 Gy at low (1 mGy/min) or high dose rate (150 mGy/min). The expression of inflammatory and thrombotic markers was quantified in frozen heart sections (CD31, E-selectin, thrombomodulin, ICAM-1, VCAM-1, collagen IV, Thy-1, and CD45) and in plasma samples (IL6, KC, MCP-1, TNF\textgreeka, INF\textgreekg, IL-1\textgreekb, TGF\textgreekb, INF\textgreekg, IL-10, sICAM-1, sE-selectin, sVCAM-1 and fibrinogen) by fluorescence analysis and ELISA. We found that even very low irradiation doses induced adaptive late responses, such as increases of capillary density and changes in collagen IV and Thy-1 levels indicating compensatory regulation. Slight decreases of ICAM-1 levels and reduction of Thy 1 expression at 0.025-0.5 Gy indicate anti-inflammatory effects, whereas at the highest dose (2 Gy) increased VCAM-1 levels on the endocardium may represent a switch to a pro-inflammatory response. Plasma samples partially confirmed this pattern, showing a decrease of proinflammatory markers (sVCAM, sICAM) at 0.025-2.0 Gy. In contrast, an enhancement of MCP-1, TNF\textgreeka and fibrinogen at 0.05-2.0 Gy indicated a proinflammatory and prothrombotic systemic response. Multivariate analysis also revealed significant age-dependent increases (KC, MCP-1, fibrinogen) and decreases (sICAM, sVCAM, sE-selectin) of plasma markers. This paper represents local and systemic effects of low-dose irradiation, including also age- and dose rate-dependent responses in the ApoE-/- mouse model. These insights in the multiple inflammatory/thrombotic effects caused by low-dose irradiation might facilitate an individual evaluation and intervention of radiation related, long-term side effects but also give important implications for low dose anti-inflammatory radiotherapy. //  Epidemiological studies indicate long-term risks of ionizing radiation on the heart, even at moderate doses. In this study, we investigated the inflammatory, thrombotic and fibrotic late responses of the heart after low-dose irradiation (IR) with specific emphasize on the dose rate. Hypercholesterolemic ApoE-deficient mice were sacrificed 3 and 6 months after total body irradiation (TBI) with 0.025, 0.05, 0.1, 0.5 or 2 Gy at low (1 mGy/min) or high dose rate (150 mGy/min). The expression of inflammatory and thrombotic markers was quantified in frozen heart sections (CD31, E-selectin, thrombomodulin, ICAM-1, VCAM-1, collagen IV, Thy-1, and CD45) and in plasma samples (IL6, KC, MCP-1, TNF\textgreeka, INF\textgreekg, IL-1\textgreekb, TGF\textgreekb, INF\textgreekg, IL-10, sICAM-1, sE-selectin, sVCAM-1 and fibrinogen) by fluorescence analysis and ELISA. We found that even very low irradiation doses induced adaptive late responses, such as increases of capillary density and changes in collagen IV and Thy-1 levels indicating compensatory regulation. Slight decreases of ICAM-1 levels and reduction of Thy 1 expression at 0.025-0.5 Gy indicate anti-inflammatory effects, whereas at the highest dose (2 Gy) increased VCAM-1 levels on the endocardium may represent a switch to a pro-inflammatory response. Plasma samples partially confirmed this pattern, showing a decrease of proinflammatory markers (sVCAM, sICAM) at 0.025-2.0 Gy. In contrast, an enhancement of MCP-1, TNF\textgreeka and fibrinogen at 0.05-2.0 Gy indicated a proinflammatory and prothrombotic systemic response. Multivariate analysis also revealed significant age-dependent increases (KC, MCP-1, fibrinogen) and decreases (sICAM, sVCAM, sE-selectin) of plasma markers. This paper represents local and systemic effects of low-dose irradiation, including also age- and dose rate-dependent responses in the ApoE-/- mouse model. These insights in the multiple inflammatory/thrombotic effects caused by low-dose irradiation might facilitate an individual evaluation and intervention of radiation related, long-term side effects but also give important implications for low dose anti-inflammatory radiotherapy.

Authors: Daniel Mathias, Ronald E J Mitchel, Mirela Barclay, Heather Wyatt, Michelle Bugden, Nicholas D. Priest, Stewart C. Whitman, Markus Scholz, Guido Hildebrandt, Manja Kamprad, Annegret Glasow, Ronald E. J. Mitchel

Date Published: 23rd Mar 2015

Publication Type: Journal article

Indications for potential parent-of-origin effects within the FTO gene
Genetical Statistics and Systems Biology

Abstract (Expand)

Genome-Wide Association Studies (GWAS) were successfully applied to discover associations with obesity. However, the GWAS design is usually based on unrelated individuals and inheritance information … on the parental origin of the alleles is missing. Taking into account parent-of-origin may provide further insights into the genetic mechanisms contributing to obesity. We hypothesized that there may be variants within the robustly replicated fat mass and obesity associated (FTO) gene that may confer different risk for obesity depending on transmission from mother or father. Genome-wide genotypes and pedigree information from the Sorbs population were used. Phased genotypes among 525 individuals were generated by AlphaImpute. Subsequently, 22 SNPs within FTO introns 1 to 3 were selected and parent-of-origin specific association analyses were performed using PLINK. Interestingly, we identified several SNPs conferring different genetic effects (P\leq0.05) depending on parental origin-among them, rs1861868, rs1121980 and rs9939973 (all in intron 1). To confirm our findings, we investigated the selected variants in 705 German trios comprising an (extremely) obese child or adolescent and both parents. Again, we observed evidence for POE effects in intron 2 and 3 (P\leq0.05) as indicated by the parental asymmetry test. Our results suggest that the obesity risk transmitted by several FTO variants may depend on the parental origin of the allele. Larger family-based studies are warranted to replicate our findings.   Genome-Wide Association Studies (GWAS) were successfully applied to discover associations with obesity. However, the GWAS design is usually based on unrelated individuals and inheritance information on the parental origin of the alleles is missing. Taking into account parent-of-origin may provide further insights into the genetic mechanisms contributing to obesity. We hypothesized that there may be variants within the robustly replicated fat mass and obesity associated (FTO) gene that may confer different risk for obesity depending on transmission from mother or father. Genome-wide genotypes and pedigree information from the Sorbs population were used. Phased genotypes among 525 individuals were generated by AlphaImpute. Subsequently, 22 SNPs within FTO introns 1 to 3 were selected and parent-of-origin specific association analyses were performed using PLINK. Interestingly, we identified several SNPs conferring different genetic effects (P\leq0.05) depending on parental origin–among them, rs1861868, rs1121980 and rs9939973 (all in intron 1). To confirm our findings, we investigated the selected variants in 705 German trios comprising an (extremely) obese child or adolescent and both parents. Again, we observed evidence for POE effects in intron 2 and 3 (P\leq0.05) as indicated by the parental asymmetry test. Our results suggest that the obesity risk transmitted by several FTO variants may depend on the parental origin of the allele. Larger family-based studies are warranted to replicate our findings. //  Genome-Wide Association Studies (GWAS) were successfully applied to discover associations with obesity. However, the GWAS design is usually based on unrelated individuals and inheritance information on the parental origin of the alleles is missing. Taking into account parent-of-origin may provide further insights into the genetic mechanisms contributing to obesity. We hypothesized that there may be variants within the robustly replicated fat mass and obesity associated (FTO) gene that may confer different risk for obesity depending on transmission from mother or father. Genome-wide genotypes and pedigree information from the Sorbs population were used. Phased genotypes among 525 individuals were generated by AlphaImpute. Subsequently, 22 SNPs within FTO introns 1 to 3 were selected and parent-of-origin specific association analyses were performed using PLINK. Interestingly, we identified several SNPs conferring different genetic effects (P\leq0.05) depending on parental origin–among them, rs1861868, rs1121980 and rs9939973 (all in intron 1). To confirm our findings, we investigated the selected variants in 705 German trios comprising an (extremely) obese child or adolescent and both parents. Again, we observed evidence for POE effects in intron 2 and 3 (P\leq0.05) as indicated by the parental asymmetry test. Our results suggest that the obesity risk transmitted by several FTO variants may depend on the parental origin of the allele. Larger family-based studies are warranted to replicate our findings.

Authors: Xuanshi Liu, Anke Hinney, Markus Scholz, André Scherag, Anke Tönjes, Michael Stumvoll, Peter F. Stadler, Johannes Hebebrand, Yvonne Böttcher

Date Published: 20th Mar 2015

Publication Type: Journal article

Monitoring Disease Progression and Therapeutic Response in a Disseminated Tumor Model for Non-Hodgkin Lymphoma by Bioluminescence Imaging
Genetical Statistics and Systems Biology

Abstract (Expand)

Xenograft tumor models are widely studied in cancer research. Our aim was to establish and apply a model for aggressive CD20-positive B-cell non-Hodgkin lymphomas, enabling us to monitor tumor growth … and shrinkage in a noninvasive manner. By stably transfecting a luciferase expression vector, we created two bioluminescent human non-Hodgkin lymphoma cell lines, Jeko1(luci) and OCI-Ly3(luci), that are CD20 positive, a prerequisite to studying rituximab, a chimeric anti-CD20 antibody. To investigate the therapy response in vivo, we established a disseminated xenograft tumor model injecting these cell lines in NOD/SCID mice. We observed a close correlation of bioluminescence intensity and tumor burden, allowing us to monitor therapy response in the living animal. Cyclophosphamide reduced tumor burden in mice injected with either cell line in a dose-dependent manner. Rituximab alone was effective in OCI-Ly3(luci)-injected mice and acted additively in combination with cyclophosphamide. In contrast, it improved the therapeutic outcome of Jeko1(luci)-injected mice only in combination with cyclophosphamide. We conclude that well-established bioluminescence imaging is a valuable tool in disseminated xenograft tumor models. Our model can be translated to other cell lines and used to examine new therapeutic agents and schedules.

Authors: Margarethe Köberle, Kristin Müller, Manja Kamprad, Friedemann Horn, Markus Scholz

Date Published: 2015

Publication Type: Journal article

Modelling chemotherapy effects on granulopoiesis.
GLA - German Lymphoma Alliance, Genetical Statistics and Systems Biology

Abstract (Expand)

BACKGROUND: Although the growth-factor G-CSF is widely used to prevent granulotoxic side effects of cytotoxic chemotherapies, its optimal use is still unknown since treatment outcome depends on many … parameters such as dosing and timing of chemotherapies, pharmaceutical derivative of G-CSF used and individual risk factors. We showed in the past that a pharmacokinetic and -dynamic model of G-CSF and human granulopoiesis can be used to predict the performance of yet untested G-CSF schedules. However, only a single chemotherapy was considered so far. RESULTS: Model assumptions proved to be feasible in explaining granulotoxicity of 10 different chemotherapeutic drugs or drug-combinations applied in 33 different schedules with and without G-CSF. Risk groups of granulotoxicity were traced back to differences in toxicity parameters. CONCLUSION: We established a comprehensive model of combined G-CSF and chemotherapy action in humans which allows us to predict and compare the outcome of alternative G-CSF schedules. We aim to apply the model in different clinical contexts to optimize and individualize G-CSF treatment.

Authors: S. Schirm, C. Engel, M. Loeffler, M. Scholz

Date Published: 24th Dec 2014

Publication Type: Not specified

Human Diseases: leukopenia

Genome wide meta-analysis highlights the role of genetic variation in RARRES2 in the regulation of circulating serum chemerin
Genetical Statistics and Systems Biology

Abstract (Expand)

Chemerin is an adipokine proposed to link obesity and chronic inflammation of adipose tissue. Genetic factors determining chemerin release from adipose tissue are yet unknown. We conducted a meta-analysis … of genome-wide association studies (GWAS) for serum chemerin in three independent cohorts from Europe: Sorbs and KORA from Germany and PPP-Botnia from Finland (total N = 2,791). In addition, we measured mRNA expression of genes within the associated loci in peripheral mononuclear cells by micro-arrays, and within adipose tissue by quantitative RT-PCR and performed mRNA expression quantitative trait and expression-chemerin association studies to functionally substantiate our loci. Heritability estimate of circulating chemerin levels was 16.2% in the Sorbs cohort. Thirty single nucleotide polymorphisms (SNPs) at chromosome 7 within the retinoic acid receptor responder 2 (RARRES2)/Leucine Rich Repeat Containing (LRRC61) locus reached genome-wide significance (p\textless5.0\times10-8) in the meta-analysis (the strongest evidence for association at rs7806429 with p = 7.8\times10-14, beta = -0.067, explained variance 2.0%). All other SNPs within the cluster were in linkage disequilibrium with rs7806429 (minimum r2 = 0.43 in the Sorbs cohort). The results of the subgroup analyses of males and females were consistent with the results found in the total cohort. No significant SNP-sex interaction was observed. rs7806429 was associated with mRNA expression of RARRES2 in visceral adipose tissue in women (p\textless0.05 after adjusting for age and body mass index). In conclusion, the present meta-GWAS combined with mRNA expression studies highlights the role of genetic variation in the RARRES2 locus in the regulation of circulating chemerin concentrations.

Authors: Anke Tönjes, Markus Scholz, Jana Breitfeld, Carola Marzi, Harald Grallert, Arnd Gross, Claes Ladenvall, Dorit Schleinitz, Kerstin Krause, Holger Kirsten, Esa Laurila, Jennifer Kriebel, Barbara Thorand, Wolfgang Rathmann, Leif Groop, Inga Prokopenko, Bo Isomaa, Frank Beutner, Jürgen Kratzsch, Joachim Thiery, Mathias Fasshauer, Nora Klöting, Christian Gieger, Matthias Blüher, Michael Stumvoll, Peter Kovacs

Date Published: 18th Dec 2014

Publication Type: Journal article

Ycasd - a tool for capturing and scaling data from graphical representations
Genetical Statistics and Systems Biology

Abstract (Expand)

BACKGROUND\backslashr\backslashnMathematical modelling of biological processes often requires a large variety of different data sets for parameter estimation and validation. It is common practice that … clinical data are not available in raw formats but are provided as graphical representations. Hence, in order to include these data into environments used for model simulations and statistical analyses, it is necessary to extract them from their presentations in the literature. For this purpose, we developed the freely available open source tool ycasd. After establishing a coordinate system by simple axes definitions, it supports convenient retrieval of data points from arbitrary figures.\backslashr\backslashnRESULTS\backslashr\backslashnAfter describing the general functionality and providing an overview of the programme interface, we demonstrate on an example how to use ycasd. A major advantage of ycasd is that it does not require a certain input file format to open and process figures. All options of ycasd are accessible through a single window which eases handling and speeds up data extraction. For subsequent processing of extracted data points, results can be formatted as a Matlab or an R matrix. We extensively compare the functionality and other features of ycasd with other publically available tools. Finally, we provide a short summary of our experiences with ycasd in the context of modelling.\backslashr\backslashnCONCLUSIONS\backslashr\backslashnWe conclude that our tool is suitable for convenient and accurate data retrievals from graphical representations such as papers. Comparison of tools reveals that ycasd is a good compromise between easy and quick capturing of scientific data from publications and complexity. Our tool is routinely applied in the context of biological modelling, where numerous time series data are required to develop models. The software can also be useful for other kinds of analyses for which published data are required but are not available in raw formats such as systematic reviews and meta-analyses. BACKGROUND Mathematical modelling of biological processes often requires a large variety of different data sets for parameter estimation and validation. It is common practice that clinical data are not available in raw formats but are provided as graphical representations. Hence, in order to include these data into environments used for model simulations and statistical analyses, it is necessary to extract them from their presentations in the literature. For this purpose, we developed the freely available open source tool ycasd. After establishing a coordinate system by simple axes definitions, it supports convenient retrieval of data points from arbitrary figures. RESULTS After describing the general functionality and providing an overview of the programme interface, we demonstrate on an example how to use ycasd. A major advantage of ycasd is that it does not require a certain input file format to open and process figures. All options of ycasd are accessible through a single window which eases handling and speeds up data extraction. For subsequent processing of extracted data points, results can be formatted as a Matlab or an R matrix. We extensively compare the functionality and other features of ycasd with other publically available tools. Finally, we provide a short summary of our experiences with ycasd in the context of modelling. CONCLUSIONS We conclude that our tool is suitable for convenient and accurate data retrievals from graphical representations such as papers. Comparison of tools reveals that ycasd is a good compromise between easy and quick capturing of scientific data from publications and complexity. Our tool is routinely applied in the context of biological modelling, where numerous time series data are required to develop models. The software can also be useful for other kinds of analyses for which published data are required but are not available in raw formats such as systematic reviews and meta-analyses. BACKGROUND Mathematical modelling of biological processes often requires a large variety of different data sets for parameter estimation and validation. It is common practice that clinical data are not available in raw formats but are provided as graphical representations. Hence, in order to include these data into environments used for model simulations and statistical analyses, it is necessary to extract them from their presentations in the literature. For this purpose, we developed the freely available open source tool ycasd. After establishing a coordinate system by simple axes definitions, it supports convenient retrieval of data points from arbitrary figures. RESULTS After describing the general functionality and providing an overview of the programme interface, we demonstrate on an example how to use ycasd. A major advantage of ycasd is that it does not require a certain input file format to open and process figures. All options of ycasd are accessible through a single window which eases handling and speeds up data extraction. For subsequent processing of extracted data points, results can be formatted as a Matlab or an R matrix. We extensively compare the functionality and other features of ycasd with other publically available tools. Finally, we provide a short summary of our experiences with ycasd in the context of modelling. CONCLUSIONS We conclude that our tool is suitable for convenient and accurate data retrievals from graphical representations such as papers. Comparison of tools reveals that ycasd is a good compromise between easy and quick capturing of scientific data from publications and complexity. Our tool is routinely applied in the context of biological modelling, where numerous time series data are required to develop models. The software can also be useful for other kinds of analyses for which published data are required but are not available in raw formats such as systematic reviews and meta-analyses. BACKGROUND Mathematical modelling of biological processes often requires a large variety of different data sets for parameter estimation and validation. It is common practice that clinical data are not available in raw formats but are provided as graphical representations. Hence, in order to include these data into environments used for model simulations and statistical analyses, it is necessary to extract them from their presentations in the literature. For this purpose, we developed the freely available open source tool ycasd. After establishing a coordinate system by simple axes definitions, it supports convenient retrieval of data points from arbitrary figures. RESULTS After describing the general functionality and providing an overview of the programme interface, we demonstrate on an example how to use ycasd. A major advantage of ycasd is that it does not require a certain input file format to open and process figures. All options of ycasd are accessible through a single window which eases handling and speeds up data extraction. For subsequent processing of extracted data points, results can be formatted as a Matlab or an R matrix. We extensively compare the functionality and other features of ycasd with other publically available tools. Finally, we provide a short summary of our experiences with ycasd in the context of modelling. CONCLUSIONS We conclude that our tool is suitable for convenient and accurate data retrievals from graphical representations such as papers. Comparison of tools reveals that ycasd is a good compromise between easy and quick capturing of scientific data from publications and complexity. Our tool is routinely applied in the context of biological modelling, where numerous time series data are required to develop models. The software can also be useful for other kinds of analyses for which published data are required but are not available in raw formats such as systematic reviews and meta-analyses.

Authors: Arnd Gross, Sibylle Schirm, Markus Scholz

Date Published: 1st Dec 2014

Publication Type: Journal article

Impact of pre-imputation SNP-filtering on genotype imputation results
Genetical Statistics and Systems Biology

Abstract (Expand)

BACKGROUND Imputation of partially missing or unobserved genotypes is an indispensable tool for SNP data analyses. However, research and understanding of the impact of initial SNP-data quality control …l on imputation results is still limited. In this paper, we aim to evaluate the effect of different strategies of pre-imputation quality filtering on the performance of the widely used imputation algorithms MaCH and IMPUTE. RESULTS We considered three scenarios: imputation of partially missing genotypes with usage of an external reference panel, without usage of an external reference panel, as well as imputation of completely un-typed SNPs using an external reference panel. We first created various datasets applying different SNP quality filters and masking certain percentages of randomly selected high-quality SNPs. We imputed these SNPs and compared the results between the different filtering scenarios by using established and newly proposed measures of imputation quality. While the established measures assess certainty of imputation results, our newly proposed measures focus on the agreement with true genotypes. These measures showed that pre-imputation SNP-filtering might be detrimental regarding imputation quality. Moreover, the strongest drivers of imputation quality were in general the burden of missingness and the number of SNPs used for imputation. We also found that using a reference panel always improves imputation quality of partially missing genotypes. MaCH performed slightly better than IMPUTE2 in most of our scenarios. Again, these results were more pronounced when using our newly defined measures of imputation quality. CONCLUSION Even a moderate filtering has a detrimental effect on the imputation quality. Therefore little or no SNP filtering prior to imputation appears to be the best strategy for imputing small to moderately sized datasets. Our results also showed that for these datasets, MaCH performs slightly better than IMPUTE2 in most scenarios at the cost of increased computing time.

Authors: Nab Raj Roshyara, Holger Kirsten, Katrin Horn, Peter Ahnert, Markus Scholz

Date Published: 1st Dec 2014

Publication Type: Journal article

Cellular Adhesion Gene SELP Is Associated with Rheumatoid Arthritis and Displays Differential Allelic Expression // Cellular adhesion gene SELP is associated with rheumatoid arthritis and displays differential allelic expression
Genetical Statistics and Systems Biology

Abstract (Expand)

In rheumatoid arthritis (RA), a key event is infiltration of inflammatory immune cells into the synovial lining, possibly aggravated by dysregulation of cellular adhesion molecules. Therefore, single … nucleotide polymorphisms of 14 genes involved in cellular adhesion processes (CAST, ITGA4, ITGB1, ITGB2, PECAM1, PTEN, PTPN11, PTPRC, PXN, SELE, SELP, SRC, TYK2, and VCAM1) were analyzed for association with RA. Association analysis was performed consecutively in three European RA family sample groups (Nfamilies = 407). Additionally, we investigated differential allelic expression, a possible functional consequence of genetic variants. SELP (selectin P, CD62P) SNP-allele rs6136-T was associated with risk for RA in two RA family sample groups as well as in global analysis of all three groups (ptotal = 0.003). This allele was also expressed preferentially (p\textless10-6) with a two- fold average increase in regulated samples. Differential expression is supported by data from Genevar MuTHER (p1 = 0.004; p2 = 0.0177). Evidence for influence of rs6136 on transcription factor binding was also found in silico and in public datasets reporting in vitro data. In summary, we found SELP rs6136-T to be associated with RA and with increased expression of SELP mRNA. SELP is located on the surface of endothelial cells and crucial for recruitment, adhesion, and migration of inflammatory cells into the joint. Genetically determined increased SELP expression levels might thus be a novel additional risk factor for RA. In rheumatoid arthritis (RA), a key event is infiltration of inflammatory immune cells into the synovial lining, possibly aggravated by dysregulation of cellular adhesion molecules. Therefore, single nucleotide polymorphisms of 14 genes involved in cellular adhesion processes (CAST, ITGA4, ITGB1, ITGB2, PECAM1, PTEN, PTPN11, PTPRC, PXN, SELE, SELP, SRC, TYK2, and VCAM1) were analyzed for association with RA. Association analysis was performed consecutively in three European RA family sample groups (Nfamilies = 407). Additionally, we investigated differential allelic expression, a possible functional consequence of genetic variants. SELP (selectin P, CD62P) SNP-allele rs6136-T was associated with risk for RA in two RA family sample groups as well as in global analysis of all three groups (ptotal = 0.003). This allele was also expressed preferentially (p\textless10-6) with a two- fold average increase in regulated samples. Differential expression is supported by data from Genevar MuTHER (p1 = 0.004; p2 = 0.0177). Evidence for influence of rs6136 on transcription factor binding was also found in silico and in public datasets reporting in vitro data. In summary, we found SELP rs6136-T to be associated with RA and with increased expression of SELP mRNA. SELP is located on the surface of endothelial cells and crucial for recruitment, adhesion, and migration of inflammatory cells into the joint. Genetically determined increased SELP expression levels might thus be a novel additional risk factor for RA.

Authors: Jana Burkhardt, Mechthild Blume, Elisabeth Petit-Teixeira, Vitor Hugo Teixeira, Anke Steiner, Elfi Quente, Grit Wolfram, Markus Scholz, Céline Pierlot, Paola Migliorini, Stefano Bombardieri, Alejandro Balsa, René Westhovens, Pilar Barrera, Timothy R D J Radstake, Helena Alves, Thomas Bardin, Bernard Prum, Frank Emmrich, François Cornelis, Peter Ahnert, Holger Kirsten

Date Published: 22nd Aug 2014

Publication Type: Journal article

A specialized post anaesthetic care unit improves fast-track management in cardiac surgery: a prospective randomized trial
Genetical Statistics and Systems Biology

Abstract (Expand)

INTRODUCTION Fast-track treatment in cardiac surgery has become the global standard of care. We compared the efficacy and safety of a specialised post-anaesthetic care unit (PACU) to a conventional …l intensive care unit (ICU) in achieving defined fast-track end-points in adult patients after elective cardiac surgery. METHODS In a prospective, single blinded, randomized study, 200 adult patients undergoing elective cardiac surgery (coronary artery bypass graft (CABG), valve surgery or combined CABG and valve surgery), were selected to receive their postoperative treatment either in the ICU (n = 100), or in the PACU (n = 100). Patients who, at the time of surgery, were in cardiogenic shock, required renal dialysis, or had an additive EuroSCORE of more than 10 were excluded from the study. The primary end points were: time to extubation (ET), and length of stay in the PACU or ICU (PACU/ICU LOS respectively). Secondary end points analysed were the incidences of: surgical re-exploration, development of haemothorax, new onset cardiac arrhythmia, low cardiac output syndrome, need for cardio-pulmonary resuscitation, stroke, acute renal failure, and death. RESULTS Median time to extubation was 90 [50; 140] min in the PACU vs. 478 [305; 643] min in the ICU group (P \textless 0.001). Median length of stay in PACU was 3.3 [2.7; 4.0] hours vs. 17.9 [10.3; 24.9] hours in the ICU (P \textless 0.001). Of the adverse events examined, only the incidence of new onset cardiac arrhythmia (25 in PACU vs. 41 in ICU, P = 0.02) was statistically different between groups. CONCLUSIONS Treatment in a specialised PACU rather than an ICU, after elective cardiac surgery leads to earlier extubation and quicker discharge to a step down unit, without compromising patient safety. TRIAL REGISTRATION ISRCTN71768341. Registered 11 March 2014.

Authors: Stefan Probst, Christof Cech, Dirk Haentschel, Markus Scholz, Joerg Ender

Date Published: 1st Aug 2014

Publication Type: Journal article

fcGENE: a versatile tool for processing and transforming SNP datasets
Genetical Statistics and Systems Biology

Abstract (Expand)

BACKGROUND Modern analysis of high-dimensional SNP data requires a number of biometrical and statistical methods such as pre-processing, analysis of population structure, association analysis and …d genotype imputation. Software used for these purposes often rely on specific and incompatible input and output data formats. Therefore extensive data management including multiple format conversions is necessary during analyses. METHODS In order to support fast and efficient management and bio-statistical quality control of high-dimensional SNP data, we developed the publically available software fcGENE using C++ object-oriented programming language. This software simplifies and automates the use of different existing analysis packages, especially during the workflow of genotype imputations and corresponding analyses. RESULTS fcGENE transforms SNP data and imputation results into different formats required for a large variety of analysis packages such as PLINK, SNPTEST, HAPLOVIEW, EIGENSOFT, GenABEL and tools used for genotype imputation such as MaCH, IMPUTE, BEAGLE and others. Data Management tasks like merging, splitting, extracting SNP and pedigree information can be performed. fcGENE also supports a number of bio-statistical quality control processes and quality based filtering processes at SNP- and sample-wise level. The tool also generates templates of commands required to run specific software packages, especially those required for genotype imputation. We demonstrate the functionality of fcGENE by example workflows of SNP data analyses and provide a comprehensive manual of commands, options and applications. CONCLUSIONS We have developed a user-friendly open-source software fcGENE, which comprehensively supports SNP data management, quality control and analysis workflows. Download statistics and corresponding feedbacks indicate that software is highly recognised and extensively applied by the scientific community.

Authors: Nab Raj Roshyara, Markus Scholz

Date Published: 22nd Jul 2014

Publication Type: Journal article

Identification of adipokine clusters related to parameters of fat mass, insulin sensitivity and inflammation
Genetical Statistics and Systems Biology

Abstract (Expand)

In obesity, elevated fat mass and ectopic fat accumulation are associated with changes in adipokine secretion, which may link obesity to inflammation and the development of insulin resistance. However, … relationships among individual adipokines and between adipokines and parameters of obesity, glucose metabolism or inflammation are largely unknown. Serum concentrations of 20 adipokines were measured in 141 Caucasian obese men (n = 67) and women (n = 74) with a wide range of body weight, glycemia and insulin sensitivity. Unbiased, distance-based hierarchical cluster analyses were performed to recognize patterns among adipokines and their relationship with parameters of obesity, glucose metabolism, insulin sensitivity and inflammation. We identified two major adipokine clusters related to either (1) body fat mass and inflammation (leptin, ANGPTL3, DLL1, chemerin, Nampt, resistin) or insulin sensitivity/hyperglycemia, and lipid metabolism (vaspin, clusterin, glypican 4, progranulin, ANGPTL6, GPX3, RBP4, DLK1, SFRP5, BMP7, adiponectin, CTRP3 and 5, omentin). In addition, we found distinct adipokine clusters in subgroups of patients with or without type 2 diabetes (T2D). Logistic regression analyses revealed ANGPTL6, DLK1, Nampt and progranulin as strongest adipokine correlates of T2D in obese individuals. The panel of 20 adipokines predicted T2D compared to a combination of HbA1c, HOMA-IR and fasting plasma glucose with lower sensitivity (78% versus 91%) and specificity (76% versus 94%). Therefore, adipokine patterns may currently not be clinically useful for the diagnosis of metabolic diseases. Whether adipokine patterns are relevant for the predictive assessment of intervention outcomes needs to be further investigated. In obesity, elevated fat mass and ectopic fat accumulation are associated with changes in adipokine secretion, which may link obesity to inflammation and the development of insulin resistance. However, relationships among individual adipokines and between adipokines and parameters of obesity, glucose metabolism or inflammation are largely unknown. Serum concentrations of 20 adipokines were measured in 141 Caucasian obese men (n = 67) and women (n = 74) with a wide range of body weight, glycemia and insulin sensitivity. Unbiased, distance-based hierarchical cluster analyses were performed to recognize patterns among adipokines and their relationship with parameters of obesity, glucose metabolism, insulin sensitivity and inflammation. We identified two major adipokine clusters related to either (1) body fat mass and inflammation (leptin, ANGPTL3, DLL1, chemerin, Nampt, resistin) or insulin sensitivity/hyperglycemia, and lipid metabolism (vaspin, clusterin, glypican 4, progranulin, ANGPTL6, GPX3, RBP4, DLK1, SFRP5, BMP7, adiponectin, CTRP3 and 5, omentin). In addition, we found distinct adipokine clusters in subgroups of patients with or without type 2 diabetes (T2D). Logistic regression analyses revealed ANGPTL6, DLK1, Nampt and progranulin as strongest adipokine correlates of T2D in obese individuals. The panel of 20 adipokines predicted T2D compared to a combination of HbA1c, HOMA-IR and fasting plasma glucose with lower sensitivity (78% versus 91%) and specificity (76% versus 94%). Therefore, adipokine patterns may currently not be clinically useful for the diagnosis of metabolic diseases. Whether adipokine patterns are relevant for the predictive assessment of intervention outcomes needs to be further investigated.

Authors: Gesine Flehmig, Markus Scholz, Nora Klöting, Mathias Fasshauer, Anke Tönjes, Michael Stumvoll, Byung-Soo Youn, Matthias Blüher, Cedric Moro

Date Published: 26th Jun 2014

Publication Type: Journal article

Impact of indication-shift of primary and adjuvant chemo radiation in advanced laryngeal and hypopharyngeal squamous cell carcinoma.
Genetical Statistics and Systems Biology

Abstract (Expand)

Based on level I evidence, postoperative platinum-based radiochemotherapy (PORCT) is the recommended standard of care in defined risk situations after resection of squamous cell carcinomas of the larynx … and hypopharynx (LHSCC). The value of the addition of chemotherapy to adjuvant radiation in intermediate and high risk situations other than extracapsular spread or R1-/R2 resection is still debated. From 1993 to 2009, 555 patients (median follow-up: 24.4 months) with advanced LHSCC (UICC stages III-IVB) were treated in a curative intent. Patient data were continuously documented in the county of Leipzig cancer registry and were retrospectively analyzed as mono institutional survey. PORCT was introduced into the standard procedures in 2004, but also applied before in selected cases. Based on this paradigm shift, the patient population was divided into two comparative groups treated before and after 2004. 361 patients were treated before 2004. 43.8 % received primary surgery (OP) + postoperative radiotherapy (PORT) and 20.2 % OP + PORCT. 194 patients were treated after 2004: 21.1 % received OP + PORT and 35.6 % OP + PORCT. Regarding the PORCT groups, 20.6 % received cisplatin plus 5FU before 2004 which shifted to 59.4 % after 2004. The 3-year tumor-specific-survival rate of the whole cohort was improved from 47 to 60 % (p = 0.006). The subgroup treated with OP + PORT or PORCT improved from 56.1 to 68.5 % (p = 0.028). Localization proved to be a significant and independent factor. Only patients with advanced laryngeal cancer had significant improved survival (p < 0.01), while the improvement for hypopharyngeal cancer patients was not significant (p < 0.2). After 2004, there was a slight increase (+10.2 %) of primary radiochemotherapy (pRCT) due to stronger selection if R0 > 5 mm-resectability is unlikely. Standardised use of PORCT and pRCT considering clear indications showed to be significantly involved in improved survival in advanced LHSCC.

Authors: A. Boehm, F. Lindner, G. Wichmann, U. Bauer, C. Wittekind, M. Knoedler, F. Lordick, S. Dietzsch, M. Scholz, R. Kortmann, A. Dietz

Date Published: 26th Jun 2014

Publication Type: Journal article

Genetic association of objective sleep phenotypes with a functional polymorphism in the neuropeptide S receptor gene
Genetical Statistics and Systems Biology

Abstract (Expand)

BACKGROUND The neuropeptide S receptor (NPSR1) and its ligand neuropeptide S (NPS) have received increased attention in the last few years, as both establish a previously unknown system of neuromodulation. …. Animal research studies have suggested that NPS may be involved in arousal/wakefulness and may also have a crucial role in sleep regulation. The single nucleotide polymorphism (SNP) rs324981 in NPSR1 has begun to shed light on a function of the NPS-system in human sleep regulation. Due to an amino acid exchange, the T-allele leads to an increased sensitivity of the NPSR1. In the only genome-wide association study to date on circadian sleep parameters in humans, an association was found between rs324981 and regular bedtime. However, the sleep parameters in this study were only measured by self-rating. Therefore, our study aimed to replicate these findings using an objective measure of sleep. METHODS The study included n = 393 white subjects (62-79 years) who participated in an actigraphic assessment for determining sleep duration, rest duration, sleep onset, rest onset and sleep onset latency. Genotyping of the SNP rs324981 was performed using the TaqMan OpenArray System. RESULTS The genotype at rs324981 was not significantly associated with rest onset (bedtime) or sleep onset (p = .146 and p = .199, respectively). However, the SNP showed a significant effect on sleep- and rest duration (p = .007 and p = .003, respectively). Subjects that were homozygous for the minor T-allele had a significantly decreased sleep- and rest duration compared to A-allele carriers. CONCLUSION The results of this study indicate that the sleep pattern in humans is influenced by the NPS-system. However, the previously reported association between bedtime and rs324981 could not be confirmed. The current finding of decreased sleep duration in T/T allele carriers is in accordance with studies in rodents reporting similar results after NPS application.

Authors: Janek Spada, Christian Sander, Ralph Burkhardt, Madlen Häntzsch, Roland Mergl, Markus Scholz, Ulrich Hegerl, Tilman Hensch

Date Published: 4th Jun 2014

Publication Type: Journal article

A combined model of human erythropoiesis and granulopoiesis under growth factor and chemotherapy treatment.
HaematoSys - Systems biology of haematopoiesis and haematopoietic neoplasia

Abstract (Expand)

BACKGROUND: Haematotoxicity of conventional chemotherapies often results in delays of treatment or reduction of chemotherapy dose. To ameliorate these side-effects, patients are routinely treated with … blood transfusions or haematopoietic growth factors such as erythropoietin (EPO) or granulocyte colony-stimulating factor (G-CSF). For the latter ones, pharmaceutical derivatives are available, which differ in absorption kinetics, pharmacokinetic and -dynamic properties. Due to the complex interaction of cytotoxic effects of chemotherapy and the stimulating effects of different growth factor derivatives, optimal treatment is a non-trivial task. In the past, we developed mathematical models of thrombopoiesis, granulopoiesis and erythropoiesis under chemotherapy and growth-factor applications which can be used to perform clinically relevant predictions regarding the feasibility of chemotherapy schedules and cytopenia prophylaxis with haematopoietic growth factors. However, interactions of lineages and growth-factors were ignored so far. RESULTS: To close this gap, we constructed a hybrid model of human granulopoiesis and erythropoiesis under conventional chemotherapy, G-CSF and EPO applications. This was achieved by combining our single lineage models of human erythropoiesis and granulopoiesis with a common stem cell model. G-CSF effects on erythropoiesis were also implemented. Pharmacodynamic models are based on ordinary differential equations describing proliferation and maturation of haematopoietic cells. The system is regulated by feedback loops partly mediated by endogenous and exogenous EPO and G-CSF. Chemotherapy is modelled by depletion of cells. Unknown model parameters were determined by fitting the model predictions to time series data of blood counts and cytokine profiles. Data were extracted from literature or received from cooperating clinical study groups. Our model explains dynamics of mature blood cells and cytokines after growth-factor applications in healthy volunteers. Moreover, we modelled 15 different chemotherapeutic drugs by estimating their bone marrow toxicity. Taking into account different growth-factor schedules, this adds up to 33 different chemotherapy regimens explained by the model. CONCLUSIONS: We conclude that we established a comprehensive biomathematical model to explain the dynamics of granulopoiesis and erythropoiesis under combined chemotherapy, G-CSF, and EPO applications. We demonstrate how it can be used to make predictions regarding haematotoxicity of yet untested chemotherapy and growth-factor schedules.

Authors: S. Schirm, C. Engel, M. Loeffler, M. Scholz

Date Published: 26th May 2014

Publication Type: Not specified

Human Diseases: leukemia, anemia

MB-COMT promoter DNA methylation is associated with working-memory processing in schizophrenia patients and healthy controls
Genetical Statistics and Systems Biology

Abstract (Expand)

Many genetic studies report mixed results both for the associations between COMT polymorphisms and schizophrenia and for the effects of COMT variants on common intermediate phenotypes of the disorder. … Reasons for this may include small genetic effect sizes and the modulation of environmental influences. To improve our understanding of the role of COMT in the disease etiology, we investigated the effect of DNA methylation in the MB-COMT promoter on neural activity in the dorsolateral prefrontal cortex during working memory processing as measured by fMRI - an intermediate phenotype for schizophrenia. Imaging and epigenetic data were measured in 102 healthy controls and 82 schizophrenia patients of the Mind Clinical Imaging Consortium (MCIC) study of schizophrenia. Neural activity during the Sternberg Item Recognition Paradigm was acquired with either a 3T Siemens Trio or 1.5T Siemens Sonata and analyzed using the FMRIB Software Library (FSL). DNA methylation measurements were derived from cryo-conserved blood samples. We found a positive association between MB-COMT promoter methylation and neural activity in the left dorsolateral prefrontal cortex in a model using a region-of-interest approach and could confirm this finding in a whole-brain model. This effect was independent of disease status. Analyzing the effect of MB-COMT promoter DNA methylation on a neuroimaging phenotype can provide further evidence for the importance of COMT and epigenetic risk mechanisms in schizophrenia. The latter may represent trans-regulatory or environmental risk factors that can be measured using brain-based intermediate phenotypes.

Authors: Esther Walton, Jingyu Liu, Johanna Hass, Tonya White, Markus Scholz, Veit Roessner, Randy Gollub, Vince D. Calhoun, Stefan Ehrlich

Date Published: 6th May 2014

Publication Type: Journal article

Impact of molecular screening for point mutations and rearrangements in routine air-dried fine-needle aspiration samples of thyroid nodules
Genetical Statistics and Systems Biology

Abstract (Expand)

BACKGROUND\backslashr\backslashnThe diagnostic limitations of thyroid fine-needle aspiration (FNA), such as the indeterminate category, can be partially overcome by molecular analyses. However, until … now, rearrangements have only been detected in fresh FNA material and the number of follicular thyroid carcinomas (FTCs) was rather low in previous studies. We aimed at investigating the impact of point mutations and rearrangement detection in a set of routine air-dried FNA smears with a higher percentage of FTCs.\backslashr\backslashnMETHODS\backslashr\backslashnRNA and DNA was extracted from 310 FNAs (164 indeterminate, 57 malignant, 89 benign) and corresponding formalin-fixed paraffin-embedded tissue (156 follicular adenomas [FAs], 32 FTCs, 44 papillary thyroid carcinomas [PTCs], 9 follicular variant PTCs, and 69 goiters). PAX8/PPARG and RET/PTC rearrangements were detected by qPCR, BRAF and RAS mutations by high-resolution melting PCR and by pyrosequencing.\backslashr\backslashnRESULTS\backslashr\backslashnForty-seven mutations were detected in the FNAs: 22 BRAF, 13 NRAS, and 3 HRAS mutations, 8 PAX8/PPARG, and one RET/PTC-rearrangement. While the presence of a BRAF and RET/PTC mutation was associated with cancer in 100% of samples each, the presence of a RAS and PAX8/PPARG mutation was associated with cancer in only 12% and 50% of samples, respectively. In the indeterminate group 4 of 25 carcinomas were identified by molecular FNA screening, which increased the sensitivity from 67% (cytology alone) to 75% (cytology plus molecular screening).\backslashr\backslashnCONCLUSION\backslashr\backslashnMolecular screening for point mutations and rearrangements is feasible in air-dried FNAs. Although the impact of detecting point mutations and rearrangements in FNAs has most likely been overestimated in previous studies, molecular FNA analyses improve presurgical diagnostics. The detection of BRAF mutations in FNA may improve the choice of surgery and postsurgical treatment. Further data are necessary to elucidate the true impact of detecting RAS and PAX8/PPARG mutations in FNAs. The inclusion of additional rare somatic mutations and miRNA markers might further improve the impact of molecular FNA diagnostics. BACKGROUND The diagnostic limitations of thyroid fine-needle aspiration (FNA), such as the indeterminate category, can be partially overcome by molecular analyses. However, until now, rearrangements have only been detected in fresh FNA material and the number of follicular thyroid carcinomas (FTCs) was rather low in previous studies. We aimed at investigating the impact of point mutations and rearrangement detection in a set of routine air-dried FNA smears with a higher percentage of FTCs. METHODS RNA and DNA was extracted from 310 FNAs (164 indeterminate, 57 malignant, 89 benign) and corresponding formalin-fixed paraffin-embedded tissue (156 follicular adenomas [FAs], 32 FTCs, 44 papillary thyroid carcinomas [PTCs], 9 follicular variant PTCs, and 69 goiters). PAX8/PPARG and RET/PTC rearrangements were detected by qPCR, BRAF and RAS mutations by high-resolution melting PCR and by pyrosequencing. RESULTS Forty-seven mutations were detected in the FNAs: 22 BRAF, 13 NRAS, and 3 HRAS mutations, 8 PAX8/PPARG, and one RET/PTC-rearrangement. While the presence of a BRAF and RET/PTC mutation was associated with cancer in 100% of samples each, the presence of a RAS and PAX8/PPARG mutation was associated with cancer in only 12% and 50% of samples, respectively. In the indeterminate group 4 of 25 carcinomas were identified by molecular FNA screening, which increased the sensitivity from 67% (cytology alone) to 75% (cytology plus molecular screening). CONCLUSION Molecular screening for point mutations and rearrangements is feasible in air-dried FNAs. Although the impact of detecting point mutations and rearrangements in FNAs has most likely been overestimated in previous studies, molecular FNA analyses improve presurgical diagnostics. The detection of BRAF mutations in FNA may improve the choice of surgery and postsurgical treatment. Further data are necessary to elucidate the true impact of detecting RAS and PAX8/PPARG mutations in FNAs. The inclusion of additional rare somatic mutations and miRNA markers might further improve the impact of molecular FNA diagnostics.

Authors: Markus Eszlinger, Annelise Krogdahl, Sina Münz, Christian Rehfeld, Eva Magrethe Precht Jensen, Carolina Ferraz, Eileen Bösenberg, Norbert Drieschner, Markus Scholz, Laszlo Hegedüs, Ralf Paschke

Date Published: 1st Feb 2014

Publication Type: Journal article

Modelling lymphoma therapy and outcome
Genetical Statistics and Systems Biology

Abstract (Expand)

Dose and time intensifications of chemotherapy improved the outcome of lymphoma therapy. However, recent study results show that too intense therapies can result in inferior tumour control. We hypothesise … that the immune system plays a key role in controlling residual tumour cells after treatment. More intense therapies result in a stronger depletion of immune cells allowing an early re-growth of the tumour.We propose a differential equations model of the dynamics and interactions of tumour and immune cells under chemotherapy. Major model features are an exponential tumour growth, a modulation of the production of effector cells by the presence of the tumour (immunogenicity), and mutual destruction of tumour and immune cells. Chemotherapy causes damage to both, immune and tumour cells. Growth rate, chemosensitivity, immunogenicity, and initial size of the tumour are assumed to be patient-specific, resulting in heterogeneity regarding therapy outcome. Maximum-entropy distributions of these parameters were estimated on the basis of clinical survival data. The resulting model can explain the outcome of five different chemotherapeutic regimens and corresponding hazard-ratios.We conclude that our model explains observed paradox effects in lymphoma therapy by the simple assumption of a relevant anti-tumour effect of the immune system. Heterogeneity of therapy outcomes can be explained by distributions of model parameters, which can be estimated on the basis of clinical survival data. We demonstrate how the model can be used to make predictions regarding yet untested therapy options.

Authors: Katja Roesch, Dirk Hasenclever, Markus Scholz

Date Published: 1st Feb 2014

Publication Type: Journal article

Validity, intra- and inter-observer reliability of automated devices for the assessment of ankle brachial index using photo-plethysmography
Genetical Statistics and Systems Biology

Abstract (Expand)

BACKGROUND\backslashr\backslashnAnkle-brachial-Index (ABI) measured by manual Dopplersonography is an easily assessable marker of global cardiovascular risk. The aim of this study was to establish novel … photo-plethysmography (PPG)-based ABI assessments in an epidemiologic context and to compare its results with those of Doppler.\backslashr\backslashnMETHODS\backslashr\backslashnTwo devices for PPG-based ABI assessments (Vicorder, Vascular Explorer) were tested and compared against Doppler in 56 putatively healthy subjects. We determined acceptance, time requirements, agreement of repeat measurements, agreement with Doppler and intra- and inter-observer concordances for both devices and compared the results. Differences between cuff inflation- and deflation-based methods were also studied for Vascular Explorer.\backslashr\backslashnRESULTS\backslashr\backslashnAcceptance was similar for both devices but Vascular Explorer was more time consuming. Agreement of multiple measurements was moderate for both methods highlighting the importance of measurement replicates. Both automated devices showed significantly higher ABI compared to Doppler which can be traced back to higher brachial pressures (Vicorder) or higher ankle pressures (Vascular Explorer). This effect is more pronounced for Vascular Explorer but can be ameliorated using the deflation method of measurement. Intra-observer concordances were similar. Inter-observer concordance was non-significantly better for Vicorder.\backslashr\backslashnCONCLUSIONS\backslashr\backslashnBoth devices proved to be feasible in epidemiologic studies, but compared to Doppler, do not constitute an advantage regarding time requirement and accuracy of ABI assessment. Since PPG-based ABI values are inflated compared to Doppler, it will be necessary to adjust Doppler-based cut-offs for risk stratification. BACKGROUND Ankle-brachial-Index (ABI) measured by manual Dopplersonography is an easily assessable marker of global cardiovascular risk. The aim of this study was to establish novel photo-plethysmography (PPG)-based ABI assessments in an epidemiologic context and to compare its results with those of Doppler. METHODS Two devices for PPG-based ABI assessments (Vicorder, Vascular Explorer) were tested and compared against Doppler in 56 putatively healthy subjects. We determined acceptance, time requirements, agreement of repeat measurements, agreement with Doppler and intra- and inter-observer concordances for both devices and compared the results. Differences between cuff inflation- and deflation-based methods were also studied for Vascular Explorer. RESULTS Acceptance was similar for both devices but Vascular Explorer was more time consuming. Agreement of multiple measurements was moderate for both methods highlighting the importance of measurement replicates. Both automated devices showed significantly higher ABI compared to Doppler which can be traced back to higher brachial pressures (Vicorder) or higher ankle pressures (Vascular Explorer). This effect is more pronounced for Vascular Explorer but can be ameliorated using the deflation method of measurement. Intra-observer concordances were similar. Inter-observer concordance was non-significantly better for Vicorder. CONCLUSIONS Both devices proved to be feasible in epidemiologic studies, but compared to Doppler, do not constitute an advantage regarding time requirement and accuracy of ABI assessment. Since PPG-based ABI values are inflated compared to Doppler, it will be necessary to adjust Doppler-based cut-offs for risk stratification.

Authors: Andrej Teren, Frank Beutner, Kerstin Wirkner, Markus Loeffler, Markus Scholz

Date Published: 1st Dec 2013

Publication Type: Journal article

Analysis of a rare functional truncating mutation rs61757459 in vaspin (SERPINA12) on circulating vaspin levels
Genetical Statistics and Systems Biology

Abstract (Expand)

UNLABELLED\backslashr\backslashnA recent genome-wide association study suggests that genetic variation within the vaspin gene might contribute to the variability in circulating serum visceral adipose … tissue-derived serine protease inhibitor (vaspin) concentrations. Here, we analyzed the functional consequences of the rare variant rs61757459 predicting a premature stop codon and its impact on circulating serum vaspin concentrations. In order to identify genetic variation, we sequenced the vaspin gene in 48 nonrelated Caucasian subjects. Rs61757459 was subsequently genotyped in three metabolically well-characterized German cohorts (N = 4,019). We addressed the impact of rs61757459 on the crystal structure of vaspin and investigated its effects on vaspin expression in vivo as well as in vitro using various cell lines (Escherichia coli, HEK293). Along with previously reported common genetic variants, sequencing of vaspin revealed a rare variant (rs61757459; minor allele frequency: 1 %) which predicts a premature stop codon p.R211X. Heterozygous carriers of this mutation had lower circulating vaspin levels when compared with noncarriers. In silico structure analysis of the truncated vaspin, which was estimated to be 24.5 kDa, suggested misfolding and potential instability due to the absence of core structural domains. Indeed, the truncated protein was detected after recombinant expression in E. coli and in lysate, but not in supernatant of HEK293 cells. We conclude that rs61757459 is a functional mutation that results in a truncated protein whose instability likely results in reduced serum vaspin levels.\backslashr\backslashnKEY MESSAGE\backslashr\backslashnA rare variant (rs61757459) in vaspin coding for the stop codon p.R211X is related to lower circulating vaspin concentrations. Structure analysis suggests misfolding and instability due to the absence of core structural domains. The truncated protein is detectable after recombinant expression in E. coli and in lysate, but not in supernatant of HEK293 cells.

Authors: Jana Breitfeld, John T. Heiker, Yvonne Böttcher, Dorit Schleinitz, Anke Tönjes, Kerstin Weidle, Kerstin Krause, E. Bartholomeus Kuettner, Markus Scholz, Wieland Kiess, Norbert Sträter, Annette G. Beck-Sickinger, Michael Stumvoll, Antje Körner, Matthias Blüher, Peter Kovacs

Date Published: 1st Nov 2013

Publication Type: Journal article

Secretory phospholipase A(2)-IIA and cardiovascular disease: a mendelian randomization study
Genetical Statistics and Systems Biology

Abstract (Expand)

OBJECTIVES\backslashr\backslashnThis study sought to investigate the role of secretory phospholipase A2 (sPLA2)-IIA in cardiovascular disease.\backslashr\backslashnBACKGROUND\backslashr\backslashnHigher … circulating levels of sPLA2-IIA mass or sPLA2 enzyme activity have been associated with increased risk of cardiovascular events. However, it is not clear if this association is causal. A recent phase III clinical trial of an sPLA2 inhibitor (varespladib) was stopped prematurely for lack of efficacy.\backslashr\backslashnMETHODS\backslashr\backslashnWe conducted a Mendelian randomization meta-analysis of 19 general population studies (8,021 incident, 7,513 prevalent major vascular events [MVE] in 74,683 individuals) and 10 acute coronary syndrome (ACS) cohorts (2,520 recurrent MVE in 18,355 individuals) using rs11573156, a variant in PLA2G2A encoding the sPLA2-IIA isoenzyme, as an instrumental variable.\backslashr\backslashnRESULTS\backslashr\backslashnPLA2G2A rs11573156 C allele associated with lower circulating sPLA2-IIA mass (38% to 44%) and sPLA2 enzyme activity (3% to 23%) per C allele. The odds ratio (OR) for MVE per rs11573156 C allele was 1.02 (95% confidence interval [CI]: 0.98 to 1.06) in general populations and 0.96 (95% CI: 0.90 to 1.03) in ACS cohorts. In the general population studies, the OR derived from the genetic instrumental variable analysis for MVE for a 1-log unit lower sPLA2-IIA mass was 1.04 (95% CI: 0.96 to 1.13), and differed from the non-genetic observational estimate (OR: 0.69; 95% CI: 0.61 to 0.79). In the ACS cohorts, both the genetic instrumental variable and observational ORs showed a null association with MVE. Instrumental variable analysis failed to show associations between sPLA2 enzyme activity and MVE.\backslashr\backslashnCONCLUSIONS\backslashr\backslashnReducing sPLA2-IIA mass is unlikely to be a useful therapeutic goal for preventing cardiovascular events.

Authors: Michael V. Holmes, Tabassome Simon, Holly J. Exeter, Lasse Folkersen, Folkert W. Asselbergs, Montse Guardiola, Jackie A. Cooper, Jutta Palmen, Jaroslav A. Hubacek, Kathryn F. Carruthers, Benjamin D. Horne, Kimberly D. Brunisholz, Jessica L. Mega, Erik P A van Iperen, Mingyao Li, Maarten Leusink, Stella Trompet, Jeffrey J W Verschuren, G. Kees Hovingh, Abbas Dehghan, Christopher P. Nelson, Salma Kotti, Nicolas Danchin, Markus Scholz, Christiane L. Haase, Dietrich Rothenbacher, Daniel I. Swerdlow, Karoline B. Kuchenbaecker, Eleonora Staines-Urias, Anuj Goel, Ferdinand van ’t Hooft, Karl Gertow, Ulf de Faire, Andrie G. Panayiotou, Elena Tremoli, Damiano Baldassarre, Fabrizio Veglia, Lesca Miriam Holdt, Frank Beutner, Ron T. Gansevoort, Gerjan J. Navis, Irene Mateo Leach, Lutz P. Breitling, Hermann Brenner, Joachim Thiery, Dhayana Dallmeier, Anders Franco-Cereceda, Jolanda M A Boer, Jeffrey W. Stephens, Marten H. Hofker, Alain Tedgui, Albert Hofman, André G. Uitterlinden, Vera Adamkova, Jan Pitha, N. Charlotte Onland-Moret, Maarten J. Cramer, Hendrik M. Nathoe, Wilko Spiering, Olaf H. Klungel, Meena Kumari, Peter H. Whincup, David A. Morrow, Peter S. Braund, Alistair S. Hall, Anders G. Olsson, Pieter A. Doevendans, Mieke D. Trip, Martin D. Tobin, Anders Hamsten, Hugh Watkins, Wolfgang Koenig, Andrew N. Nicolaides, Daniel Teupser, Ian N M Day, John F. Carlquist, Tom R. Gaunt, Ian Ford, Naveed Sattar, Sotirios Tsimikas, Gregory G. Schwartz, Debbie A. Lawlor, Richard W. Morris, Manjinder S. Sandhu, Rudolf Poledne, Anke H Maitland-van der Zee, Kay-Tee Khaw, Brendan J. Keating, Pim van der Harst, Jackie F. Price, Shamir R. Mehta, Salim Yusuf, Jaqueline C M Witteman, Oscar H. Franco, J. Wouter Jukema, Peter de Knijff, Anne Tybjaerg-Hansen, Daniel J. Rader, Martin Farrall, Nilesh J. Samani, Mika Kivimaki, Keith A A Fox, Steve E. Humphries, Jeffrey L. Anderson, S. Matthijs Boekholdt, Tom M. Palmer, Per Eriksson, Guillaume Paré, Aroon D. Hingorani, Marc S. Sabatine, Ziad Mallat, Juan P. Casas, Philippa J. Talmud

Date Published: 1st Nov 2013

Publication Type: Journal article

Behandlung der Patienten mit einem Venenastverschluss in Abhängigkeit von der Verschlussdauer
Genetical Statistics and Systems Biology

Abstract (Expand)

PURPOSE\backslashr\backslashnThe aim of this study was to evaluate the effects of intravitreal treatment with bevacizumab (IVB) compared with triamcinolone (IVT) in patients with macular edema due to … branch retinal vein occlusion (BRVO) depending on the duration of BRVO.\backslashr\backslashnMETHODS\backslashr\backslashnA total of 65 BRVO patients were divided into 2 subgroups: group 1 with early treatment (≤ 3 months since onset of BRVO) and group 2 with late treatment (\textgreater 3 months since onset). For the two groups IVB was injected into 17 eyes as early (IVB1) and into 18 eyes as late (IVB2) treatment. For comparison IVT was injected into 14 eyes as early (IVT1) and into 16 eyes as late (IVT2) treatment. Best corrected visual acuity (BCVA) and central retinal thickness (CRT) were analyzed at baseline, 1, 3 and 6 months after treatment.\backslashr\backslashnRESULTS\backslashr\backslashnIn both subgroups a significant improvement of BCVA and CRwas observed. After 6 months, for patients with early treatment, IVB1 showed better results than IVT1 (BCVA: p = 0.008, CRT: p = 0.021). In the late treatment no significant differences between IVT2 and IVB2 were found.\backslashr\backslashnCONCLUSIONS\backslashr\backslashnBevacizumab and triamcinolone significantly improved BCVA and CRT in patients with BRVO. The best BCVA was found if bevacizumab was used as early treatment. In the late treatment no significant differences between bevacizumab and triamcinolone were observed.

Authors: Matus Rehak, E. Spies, Markus Scholz, Peter Wiedemann

Date Published: 1st Oct 2013

Publication Type: Journal article

The role of rs2237781 within GRM8 in eating behavior
Genetical Statistics and Systems Biology

Abstract (Expand)

Introduction:The glutamate receptor, metabotropic 8 gene (GRM8) encodes a G-protein-coupled glutamate receptor and has been associated with smoking behavior and liability to alcoholism implying a role … in addiction vulnerability. Data from animal studies suggest that GRM8 may be involved in the regulation of the neuropeptide Y and melanocortin pathways and might influence food intake and metabolism. This study aimed to investigate the effects of the genetic variant rs2237781 within GRM8 on human eating behavior. Methods:The initial analysis included 548 Sorbs from Germany who have been extensively phenotyped for metabolic traits and who completed the German version of the three-factor eating questionnaire. In addition, we analyzed two independent sample sets comprising 293 subjects from another German cohort and 430 Old Order Amish individuals. Genetic associations with restraint, disinhibition, and hunger were assessed in an additive linear regression model. Results:Among the Sorbs the major G allele of rs2237781 was significantly associated with increased restraint scores in eating behavior (P = 1.9 \times 10(-4); \textgreekb = +1.936). The German cohort and the Old Order Amish population revealed a trend in the same direction for restraint (P = 0.242; \textgreekb = +0.874; P = 0.908; \textgreekb = +0.096; respectively). A meta-analysis resulted in a combined P = 3.1 \times 10(-3) (Z-score 2.948). Conclusion:Our data suggest that rs2237781 within GRM8 may influence human eating behavior factors probably via pathways involved in addictive behavior.

Authors: Marie-Therese Gast, Anke Tönjes, Maria Keller, Annette Horstmann, Nanette Steinle, Markus Scholz, Ines Müller, Arno Villringer, Michael Stumvoll, Peter Kovacs, Yvonne Böttcher

Date Published: 1st Sep 2013

Publication Type: Journal article

Comparison and modelling of pegylated or unpegylated G-CSF schedules in CHOP-14 regimen of elderly patients with aggressive B-cell lymphoma.
GLA - German Lymphoma Alliance, Genetical Statistics and Systems Biology

Abstract (Expand)

Bi-weekly (R)-CHOP therapy is one of the standard treatmentS for elderly patients with aggressive B-cell lymphoma, but it is only feasible with supportive G-CSF treatment. In the trials of the DSHNHL, … either unpegylated G-CSF was given daily over 7 or 10 days or pegylated G-CSF was applied at day 4 of each cycle. These schedules were planned on the basis of simulations of a biomathematical pharmacokinetic/pharmacodynamic model. By analysing the observed data, we investigated whether our model predictions were correct and whether even better schedules can be proposed. We used data on 249 matched patients of two prospective trials, RICOVER-60 and PEGFILGRASTIM. The three G-CSF-schedules showed similar outcomes regarding leukocytopenia, infections and days in hospital, with pegylated G-CSF having slightly but not significantly better scores in all three endpoints. Regarding pegylated G-CSF, the best timing is predicted to be any day between days 4 and 7. With respect to unpegylated G-CSF, the starting day is less important, but it should be continued until the end of each cycle.The three G-CSF-schedules are interchangeable in (R)-CHOP-14 for elderly patients with aggressive B-cell lymphoma. Our model correctly predicts time courses of leukocytes. Further model predictions are presented, which can be tested in subsequent clinical trials.

Authors: S. Zeynalova, M. Ziepert, M. Scholz, S. Schirm, C. Zwick, M. Pfreundschuh, M. Loeffler

Date Published: 30th Jul 2013

Publication Type: Not specified

Human Diseases: B-cell lymphoma

Mice overexpressing CD97 in intestinal epithelial cells provide a unique model for mammalian postnatal intestinal cylindrical growth
Genetical Statistics and Systems Biology

Abstract (Expand)

Postnatal enlargement of the mammalian intestine comprises cylindrical and luminal growth, associated with crypt fission and crypt/villus hyperplasia, respectively, which subsequently predominate before … and after weaning. The bipartite adhesion G protein-coupled receptor CD97 shows an expression gradient along the crypt-villus axis in the normal human intestine. We here report that transgenic mice overexpressing CD97 in intestinal epithelial cells develop an upper megaintestine. Intestinal enlargement involves an increase in length and diameter but does not affect microscopic morphology, as typical for cylindrical growth. The megaintestine is acquired after birth and before weaning, independent of the genotype of the mother, excluding altered availability of milk constituents as driving factor. CD97 overexpression does not regulate intestinal growth factors, stem cell markers, and Wnt signaling, which contribute to epithelial differentiation and renewal, nor does it affect suckling-to-weaning transition. Consistent with augmented cylindrical growth, suckling but not adult transgenic mice show enlarged crypts and thus more crypt fissions caused by a transient increase of the crypt transit-amplifying zone. Intestinal enlargement by CD97 requires its seven-span transmembrane/cytoplasmic C-terminal fragment but not the N-terminal fragment binding partner CD55. In summary, ectopic expression of CD97 in intestinal epithelial cells provides a unique model for intestinal cylindrical growth occurring in breast-fed infants.

Authors: Gabriela Aust, Christiane Kerner, Susann Gonsior, Doreen Sittig, Hartmut Schneider, Peter Buske, Markus Scholz, Norman Dietrich, Sindy Oldenburg, Olga N. Karpus, Jörg Galle, Salah Amasheh, Jörg Hamann

Date Published: 15th Jul 2013

Publication Type: Journal article

Alu elements in ANRIL non-coding RNA at chromosome 9p21 modulate atherogenic cell functions through trans-regulation of gene networks
Genetical Statistics and Systems Biology

Abstract (Expand)

The chromosome 9p21 (Chr9p21) locus of coronary artery disease has been identified in the first surge of genome-wide association and is the strongest genetic factor of atherosclerosis known today. … Chr9p21 encodes the long non-coding RNA (ncRNA) antisense non-coding RNA in the INK4 locus (ANRIL). ANRIL expression is associated with the Chr9p21 genotype and correlated with atherosclerosis severity. Here, we report on the molecular mechanisms through which ANRIL regulates target-genes in trans, leading to increased cell proliferation, increased cell adhesion and decreased apoptosis, which are all essential mechanisms of atherogenesis. Importantly, trans-regulation was dependent on Alu motifs, which marked the promoters of ANRIL target genes and were mirrored in ANRIL RNA transcripts. ANRIL bound Polycomb group proteins that were highly enriched in the proximity of Alu motifs across the genome and were recruited to promoters of target genes upon ANRIL over-expression. The functional relevance of Alu motifs in ANRIL was confirmed by deletion and mutagenesis, reversing trans-regulation and atherogenic cell functions. ANRIL-regulated networks were confirmed in 2280 individuals with and without coronary artery disease and functionally validated in primary cells from patients carrying the Chr9p21 risk allele. Our study provides a molecular mechanism for pro-atherogenic effects of ANRIL at Chr9p21 and suggests a novel role for Alu elements in epigenetic gene regulation by long ncRNAs.

Authors: Lesca Miriam Holdt, Steve Hoffmann, Kristina Sass, David Langenberger, Markus Scholz, Knut Krohn, Knut Finstermeier, Anika Stahringer, Wolfgang Wilfert, Frank Beutner, Stephan Gielen, Gerhard Schuler, Gábor Gäbel, Hendrik Bergert, Ingo Bechmann, Peter F. Stadler, Joachim Thiery, Daniel Teupser

Date Published: 4th Jul 2013

Publication Type: Journal article

A Genome-Wide Association Study Suggests Novel Loci Associated with a Schizophrenia-Related Brain-Based Phenotype
Genetical Statistics and Systems Biology

Abstract (Expand)

Patients with schizophrenia and their siblings typically show subtle changes of brain structures, such as a reduction of hippocampal volume. Hippocampal volume is heritable, may explain a variety of … cognitive symptoms of schizophrenia and is thus considered an intermediate phenotype for this mental illness. The aim of our analyses was to identify single-nucleotide polymorphisms (SNP) related to hippocampal volume without making prior assumptions about possible candidate genes. In this study, we combined genetics, imaging and neuropsychological data obtained from the Mind Clinical Imaging Consortium study of schizophrenia (n = 328). A total of 743,591 SNPs were tested for association with hippocampal volume in a genome-wide association study. Gene expression profiles of human hippocampal tissue were investigated for gene regions of significantly associated SNPs. None of the genetic markers reached genome-wide significance. However, six highly correlated SNPs (rs4808611, rs35686037, rs12982178, rs1042178, rs10406920, rs8170) on chromosome 19p13.11, located within or in close proximity to the genes NR2F6, USHBP1, and BABAM1, as well as four SNPs in three other genomic regions (chromosome 1, 2 and 10) had p-values between 6.75\times10(-6) and 8.3\times10(-7). Using existing data of a very recently published GWAS of hippocampal volume and additional data of a multicentre study in a large cohort of adolescents of European ancestry, we found supporting evidence for our results. Furthermore, allelic differences in rs4808611 and rs8170 were highly associated with differential mRNA expression in the cis-acting region. Associations with memory functioning indicate a possible functional importance of the identified risk variants. Our findings provide new insights into the genetic architecture of a brain structure closely linked to schizophrenia. In silico replication, mRNA expression and cognitive data provide additional support for the relevance of our findings. Identification of causal variants and their functional effects may unveil yet unknown players in the neurodevelopment and the pathogenesis of neuropsychiatric disorders.

Authors: Johanna Hass, Esther Walton, Holger Kirsten, Jingyu Liu, Lutz Priebe, Christiane Wolf, Nazanin Karbalai, Randy Gollub, Tonya White, Veit Roessner, Kathrin U. Müller, Tomas Paus, Michael N. Smolka, Gunter Schumann, Markus Scholz, Sven Cichon, Vince D. Calhoun, Stefan Ehrlich

Date Published: 21st Jun 2013

Publication Type: Journal article

A biomathematical model of human erythropoiesis under erythropoietin and chemotherapy administration.
HaematoSys - Systems biology of haematopoiesis and haematopoietic neoplasia

Abstract (Expand)

Anaemia is a common haematologic side effect of dose-dense multi-cycle cytotoxic polychemotherapy requiring erythrocyte transfusions or erythropoietin (EPO) administration. To simulate the effectiveness … of different EPO application schedules, we performed both modelling of erythropoiesis under chemotherapy and pharmacokinetic and dynamic modelling of EPO applications in the framework of a single comprehensive biomathematical model. For this purpose, a cell kinetic model of bone marrow erythropoiesis was developed that is based on a set of differential compartment equations describing proliferation and maturation of erythropoietic cell stages. The system is regulated by several feedback loops comprising those mediated by EPO. We added a model of EPO absorption after injection at different sites and a pharmacokinetic model of EPO derivatives to account for the effects of external EPO applications. Chemotherapy is modelled by a transient depletion of bone marrow cell stages. Unknown model parameters were determined by fitting the predictions of the model to data sets of circulating erythrocytes, haemoglobin, haematocrit, percentage of reticulocytes or EPO serum concentrations derived from the literature or cooperating clinical study groups. Parameter fittings resulted in a good agreement of model and data. Depending on site of injection and derivative (Alfa, Beta, Delta, Darbepoetin), nine groups of EPO applications were distinguished differing in either absorption kinetics or pharmacokinetics. Finally, eight different chemotherapy protocols were modelled. The model was validated on the basis of scenarios not used for parameter fitting. Simulations were performed to analyze the impact of EPO applications on the risk of anaemia during chemotherapy. We conclude that we established a model of erythropoiesis under chemotherapy that explains a large set of time series data under EPO and chemotherapy applications. It allows predictions regarding yet untested EPO schedules. Prospective clinical studies are needed to validate model predictions and to explore the feasibility and effectiveness of the proposed schedules.

Authors: S. Schirm, C. Engel, M. Loeffler, M. Scholz

Date Published: 12th Jun 2013

Publication Type: Not specified

Human Diseases: anemia

The vacuum phenomenon in intervertebral disc disease of dogs based on computed tomography images
Genetical Statistics and Systems Biology

Abstract (Expand)

OBJECTIVES\backslashr\backslashnVacuum phenomenon is suspected to be indicative of disc degeneration and subsequent herniation. The objective of this study was to assess the reliability of vacuum … phenomenon for identification of herniated discs causing neurological signs. Prevalence of vacuum phenomenon and influencing factors in dogs with disc herniation were determined.\backslashr\backslashnMETHODS\backslashr\backslashnRetrospective review of computed tomography scans from dogs with suspected disc herniation for the presence of gas within intervertebral disc space with subsequent comparison of vacuum phenomenon and herniated disc as confirmed by surgery. Subgroups were created (chondrodystrophic, non-chondrodystrophic and unknown classification) to analyse prevalence and influencing factors (age, breed and gender) for vacuum phenomenon and agreement with herniated disc.\backslashr\backslashnRESULTS\backslashr\backslashnPrevalence of vacuum phenomenon in all dogs, chondrodystrophic, non-chondrodystrophic dogs and those with unknown classification was 19·8, 14·9, 35·7 and 24·5%, respectively. Corresponding correlation rate between vacuum phenomenon and herniated disc was 64, 67, 40 and 82%. Prevalence of vacuum phenomenon was significantly higher in nonchondrodystrophic dogs (P=0·04). Age was the only factor influencing prevalence of vacuum phenomenon (P=0·04).\backslashr\backslashnCLINICAL SIGNIFICANCE\backslashr\backslashnIn dogs with intervertebral disc disease, vacuum phenomenon is a frequent but inconsistent finding. Although helpful to identify degenerated discs, it is not suitable to identify currently herniated disc with sufficient accuracy.

Authors: M. K. Müller, E. Ludewig, G. Oechtering, Markus Scholz, T. Flegel

Date Published: 1st May 2013

Publication Type: Journal article

Seminal plasma adipokine levels are correlated with functional characteristics of spermatozoa
Genetical Statistics and Systems Biology

Abstract (Expand)

OBJECTIVE\backslashr\backslashnTo study adipokines as a potential link between obesity and male subfertility.\backslashr\backslashnDESIGN\backslashr\backslashnCross-sectional study of subjects stratified … into subgroups according to body mass index (BMI): normal-weight (18.50-24.99 kg/m(2)), overweight (25-29.99 kg/m(2)), and obese (\textgreater30 kg/m(2)).\backslashr\backslashnSETTING\backslashr\backslashnLeipzig, Germany from 2007 to 2011.\backslashr\backslashnPATIENT(S)\backslashr\backslashnNinety-six male volunteers without spermatogenesis-associated diseases.\backslashr\backslashnINTERVENTION(S)\backslashr\backslashnNone.\backslashr\backslashnMAIN OUTCOME MEASURE(S)\backslashr\backslashnSemen parameters, reproductive hormones in serum, and leptin, adiponectin, resistin, chemerin, progranulin, vaspin, and visfatin concentrations in serum and seminal plasma.\backslashr\backslashnRESULT(S)\backslashr\backslashnAll measured adipokines were detectable in human seminal plasma. The levels of progranulin, visfatin, and vaspin were statistically significantly higher in seminal plasma than in serum. An increase in body weight was associated with decreased levels of seminal plasma progranulin. Additionally, overweight/obese men had statistically significantly lower progranulin levels in seminal plasma than normal weight men. Adiponectin and progranulin concentrations in seminal plasma statistically significantly positively correlated with sperm concentration, sperm count, and total normomorphic spermatozoa.\backslashr\backslashnCONCLUSION(S)\backslashr\backslashnAdipokines are differently regulated in human male reproductive tract compared with the peripheral blood, and they could influence sperm functionality.

Authors: Stephanie Thomas, Dorothea Kratzsch, Michael Schaab, Markus Scholz, Sonja Grunewald, Joachim Thiery, Uwe Paasch, Jürgen Kratzsch

Date Published: 1st Apr 2013

Publication Type: Journal article

Comparing measures of association in 2x2 probability tables
Genetical Statistics and Systems Biology

Abstract

Not specified

Authors: Dirk Hasenclever, Markus Scholz

Date Published: 2013

Publication Type: Journal article

Merging concepts - coupling an agent-based model of hematopoietic stem cells with an ODE model of granulopoiesis
Genetical Statistics and Systems Biology

Abstract (Expand)

BACKGROUND\backslashr\backslashnHematopoiesis is a complex process involving different cell types and feedback mechanisms mediated by cytokines. This complexity stimulated various models with different … scopes and applications. A combination of complementary models promises to provide their mutual confirmation and to explain a broader range of scenarios. Here we propose a combination of an ordinary differential equation (ODE) model of human granulopoiesis and an agent-based model (ABM) of hematopoietic stem cell (HSC) organization. The first describes the dynamics of bone marrow cell stages and circulating cells under various perturbations such as G-CSF treatment or chemotherapy. In contrast to the ODE model describing cell numbers, our ABM focuses on the organization of individual cells in the stem population.\backslashr\backslashnRESULTS\backslashr\backslashnWe combined the two models by replacing the HSC compartment of the ODE model by a difference equation formulation of the ABM. In this hybrid model, regulatory mechanisms and parameters of the original models were kept unchanged except for a few specific improvements: (i) Effect of chemotherapy was restricted to proliferating HSC and (ii) HSC regulation in the ODE model was replaced by the intrinsic regulation of the ABM. Model simulations of bleeding, chronic irradiation and stem cell transplantation revealed that the dynamics of hybrid and ODE model differ markedly in scenarios with stem cell damage. Despite these differences in response to stem cell damage, both models explain clinical data of leukocyte dynamics under four chemotherapy regimens.\backslashr\backslashnCONCLUSIONS\backslashr\backslashnABM and ODE model proved to be compatible and were combined without altering the structure of both models. The new hybrid model introduces model improvements by considering the proliferative state of stem cells and enabling a cell cycle-dependent effect of chemotherapy. We demonstrated that it is able to explain and predict granulopoietic dynamics for a large variety of scenarios such as irradiation, bone marrow transplantation, chemotherapy and growth factor applications. Therefore, it promises to serve as a valuable tool for studies in a broader range of clinical applications, in particular where stem cell activation and proliferation are involved.

Authors: Axel Krinner, Ingo Roeder, Markus Loeffler, Markus Scholz

Date Published: 2013

Publication Type: Journal article

The management of thyroid nodules: a retrospective analysis of health insurance data
Genetical Statistics and Systems Biology

Abstract (Expand)

BACKGROUND\backslashr\backslashnIn Germany, about 59 000 thyroid operations are performed each year for uni- or multinodular goiter, most of them for diagnostic purposes. The rate of detection of thyroid … cancer in such operations is relatively low, at 1:15. Evidence suggests that the preoperative tests recommended in guidelines for estimating the risk of cancer are not being performed as often as they should. In the present study, we determined the measures that were actually taken to diagnose and treat thyroid nodules and compared the findings with the guideline recommendations.\backslashr\backslashnMETHOD\backslashr\backslashnWe retrospectively analyzed data from a single, large statutory healthinsurance carrier in Germany (AOK), determining the diagnostic and therapeutic measures that were reimbursed for 25 600 patients in whom a uni- or multinodular goiter was newly diagnosed in the second quarter of 2006 (none of these patients had carried such a diagnosis 1 year previously). We recorded the diagnostic measures performed in the preceding 9 months and all other tests and treatments, including surgery and radioactive iodine treatment, in the 2 years thereafter.\backslashr\backslashnRESULTS\backslashr\backslashnAmong patients who underwent surgery for uninodular goiter, the preoperative diagnostic studies included ultrasonography (in 100% of patients), scintigraphy (94%), measurement of thyroid-stimulating hormone (95%), measurement of calcitonin (9%), and fine-needle aspiration cytology (FNAC)(21%). An ultrasonographic examination was billed for only 28% of patients with uninodular goiter in the two years after the diagnosis was made. 13% of patients with uninodular goiter who were not operated on were given L-thyroxine, even though this is against guideline recommendations.\backslashr\backslashnCONCLUSION\backslashr\backslashnInadequate preoperative risk stratification of thyroid nodules may explain the large number of thyroid operations that are performed for diagnostic purposes, resulting in a low percentage of malignancies detected. Preoperative FNAC and calcitonin measurement should be used in the diagnostic evaluation of thyroid nodules far more often than this is now done. As a rule, follow-up ultrasonography should be performed for all thyroid nodules that are not operated on. Patients with non-operated thyroid nodules should not be given thyroxine. A limitation of this study is that diagnostic measures were only recorded if they were performed in the 9 months before surgery, with earlier diagnostic measures (if any) being missed.

Authors: Romy Wienhold, Markus Scholz, Jürgen-Bernhard Adler, Christian Günster, Ralf Paschke

Date Published: 2013

Publication Type: Journal article

Pharmacokinetic and -dynamic modelling of G-CSF derivatives in humans
Genetical Statistics and Systems Biology

Abstract (Expand)

BACKGROUND\backslashr\backslashnThe human granulocyte colony-stimulating factor (G-CSF) is routinely applied to support recovery of granulopoiesis during the course of cytotoxic chemotherapies. However, … optimal use of the drug is largely unknown. We showed in the past that a biomathematical compartment model of human granulopoiesis can be used to make clinically relevant predictions regarding new, yet untested chemotherapy regimen. In the present paper, we aim to extend this model by a detailed pharmacokinetic and -dynamic modelling of two commonly used G-CSF derivatives Filgrastim and Pegfilgrastim.\backslashr\backslashnRESULTS\backslashr\backslashnModel equations are based on our physiological understanding of the drugs which are delayed absorption of G-CSF when applied to the subcutaneous tissue, dose-dependent bioavailability, unspecific first order elimination, specific elimination in dependence on granulocyte counts and reversible protein binding. Pharmacokinetic differences between Filgrastim and Pegfilgrastim were modelled as different parameter sets. Our former cell-kinetic model of granulopoiesis was essentially preserved, except for a few additional assumptions and simplifications. We assumed a delayed action of G-CSF on the bone marrow, a delayed action of chemotherapy and differences between Filgrastim and Pegfilgrastim with respect to stimulation potency of the bone marrow. Additionally, we incorporated a model of combined action of Pegfilgrastim and Filgrastim or endogenous G-CSF which interact via concurrent receptor binding. Unknown pharmacokinetic or cell-kinetic parameters were determined by fitting the predictions of the model to available datasets of G-CSF applications, chemotherapy applications or combinations of it. Data were either extracted from the literature or were received from cooperating clinical study groups. Model predictions fitted well to both, datasets used for parameter estimation and validation scenarios as well. A unique set of parameters was identified which is valid for all scenarios considered. Differences in pharmacokinetic parameter estimates between Filgrastim and Pegfilgrastim were biologically plausible throughout.\backslashr\backslashnCONCLUSION\backslashr\backslashnWe conclude that we established a comprehensive biomathematical model to explain the dynamics of granulopoiesis under chemotherapy and applications of two different G-CSF derivatives. We aim to apply the model to a large variety of chemotherapy regimen in the future in order to optimize corresponding G-CSF schedules or to individualize G-CSF treatment according to the granulotoxic risk of a patient.

Authors: Markus Scholz, Sibylle Schirm, Marcus Wetzler, Christoph Engel, Markus Loeffler

Date Published: 1st Dec 2012

Publication Type: Journal article

Impact of age on the efficacy of bone marrow mononuclear cell transplantation in experimental stroke
Genetical Statistics and Systems Biology

Abstract (Expand)

Bone marrow-derived mononuclear cells (BM MNC) have been effectively used to treat experimental stroke. Most of the preclinical trials have been performed in young and healthy laboratory animals, even … though age and hypertension are major risk factors for stroke. To determine the influence of age on the properties of BM MNCs after cerebral ischemia, we compared the efficacy of aged and young BM MNC in an in vitro model of cerebral hypoxia and in an adapted in vivo model of stroke. Human BM MNCs were obtained from healthy young or aged donors and either co-cultured with rat hippocampal slices exposed to oxygen glucose deprivation (OGD), or transplanted intravenously 24 h after permanent middle cerebral artery occlusion in aged (18 months) spontaneously hypertensive rats (SHR). Efficacy was examined by quantification of hippocampal cell death, or respectively, by neurofunctional tests and MR investigations. Co-cultivation with young, but not with aged BM MNCs significantly reduced the hippocampal cell death after OGD. Transplantation of both young and old BM MNCs did not reduce functional deficits or ischemic lesion volume after stroke in aged SHR. These results suggest a significant impact of age on the therapeutic efficacy of BM MNCs after cerebral ischemia.

Authors: Daniel-Christoph Wagner, Mitja Bojko, Myriam Peters, Marlene Lorenz, Cornelia Voigt, Alexander Kaminski, Dirk Hasenclever, Markus Scholz, Alexander Kranz, Gesa Weise, Johannes Boltze

Date Published: 1st Dec 2012

Publication Type: Journal article

Automated photoplethysmography-based determination of ankle-brachial index: a validation study against Doppler sonography
Genetical Statistics and Systems Biology

Abstract (Expand)

INTRODUCTION\backslashr\backslashnDetermination of ankle-brachial-index (ABI) by manual Doppler is well established to screen for lower extremity arterial disease (LEAD) and to predict cardiovascular … risk. A new generation of digital-controlled devices promises automated ABI determination. The aim of this study was to determine comparability of automated photoplethysmography (PPG)-derived ABI calculation with the Doppler-ABI algorithm commonly used in cohort studies.\backslashr\backslashnMETHODS\backslashr\backslashnAutomated PPG-based ABI measurements [Vascular Explorer (VE) and Vicorder (VI)] were recorded from 112 limbs of healthy subjects and 22 limbs of patients with confirmed LEAD. Validity was evaluated on the basis of receiver-operating characteristic (ROC) analysis of clinical status and concordance with Doppler-ABI. Differences between cuff inflation [inf]- and deflation [def]-based method were studied in VE.\backslashr\backslashnRESULTS\backslashr\backslashnPPG-based ABI values were higher compared to Doppler-ABI (VI +0.06, VEinf +0.15, VEdef +0.09, p \textless 0.001, respectively). The difference was pronounced in pathological (\textless0.9), borderline (0.9-0.99) and low normal (1.0-1.09) ABI, but less in ABI \geq1.1. However, ROC analysis revealed excellent diagnostic value for LEAD (sensitivity/specificity) and comparable area under the curve at method-adapted ABI thresholds for all methods: Doppler (95/90 %, 0.95), VI (75/96 %, 0.91), VEinf (85/89 %, 0.93) and VEdef (80/98 %, 0.94).\backslashr\backslashnCONCLUSIONS\backslashr\backslashnDigital-controlled PPG-based ABI determination is a useful diagnostic application for LEAD. However, the systematic higher ABI in PPG-based measurement compared to Doppler and remarkable differences between the deflationary and inflationary method are critical for the interpretation of borderline and low normal ABI values where precise reading is essential to detect mild LEAD and subclinical disease and to predict cardiovascular risk. INTRODUCTION Determination of ankle-brachial-index (ABI) by manual Doppler is well established to screen for lower extremity arterial disease (LEAD) and to predict cardiovascular risk. A new generation of digital-controlled devices promises automated ABI determination. The aim of this study was to determine comparability of automated photoplethysmography (PPG)-derived ABI calculation with the Doppler-ABI algorithm commonly used in cohort studies. METHODS Automated PPG-based ABI measurements [Vascular Explorer (VE) and Vicorder (VI)] were recorded from 112 limbs of healthy subjects and 22 limbs of patients with confirmed LEAD. Validity was evaluated on the basis of receiver-operating characteristic (ROC) analysis of clinical status and concordance with Doppler-ABI. Differences between cuff inflation [inf]- and deflation [def]-based method were studied in VE. RESULTS PPG-based ABI values were higher compared to Doppler-ABI (VI +0.06, VEinf +0.15, VEdef +0.09, p \textless 0.001, respectively). The difference was pronounced in pathological (\textless0.9), borderline (0.9-0.99) and low normal (1.0-1.09) ABI, but less in ABI \geq1.1. However, ROC analysis revealed excellent diagnostic value for LEAD (sensitivity/specificity) and comparable area under the curve at method-adapted ABI thresholds for all methods: Doppler (95/90 %, 0.95), VI (75/96 %, 0.91), VEinf (85/89 %, 0.93) and VEdef (80/98 %, 0.94). CONCLUSIONS Digital-controlled PPG-based ABI determination is a useful diagnostic application for LEAD. However, the systematic higher ABI in PPG-based measurement compared to Doppler and remarkable differences between the deflationary and inflationary method are critical for the interpretation of borderline and low normal ABI values where precise reading is essential to detect mild LEAD and subclinical disease and to predict cardiovascular risk.

Authors: Frank Beutner, Andrej Teren, Stephan Gielen, Gerhard Schuler, Kerstin Wirkner, Daniel Tiller, Markus Loeffler, Markus Scholz

Date Published: 1st Nov 2012

Publication Type: Journal article

"Real-time-3-dimensional-full-volume"-datensatz: Nutzen in der problemfokussierten intraoperativen transösophagealen echokardiographie
Genetical Statistics and Systems Biology

Abstract (Expand)

BACKGROUND\backslashr\backslashnComprehensive intraoperative transesophageal echcardiography (TEE) includes various measurements for quantification of cardiac chambers and valves based on multiple two … dimensional (2D) standard views. Due to shortness of time during cardiac surgery most centres in Germany only carry out problem focussed intraoperative examinations which does not allow the complete repertoire of measurements to be exhausted. The aim of this study was to investigate which measurements for cardiac chamber and valve quantification can be performed with the acquisition of a real-time 3D full volume (RT-3D-FV) data set and to compare these measurements with those based on standard 2D views.\backslashr\backslashnMATERIALS AND METHODS\backslashr\backslashnIn patients undergoing elective surgical mitral valve repair a comprehensive 2D TEE examination according to the guidelines of the American Society of Echocardiography (ASE) and the Society of Cardiovascular Anesthesiologists (SCA) was performed after induction of anesthesia. Additionally, a RT-3D-FV TEE data set based on the midesophageal four chamber view was recorded (iE 33, Philips, Netherlands). All measurements of the 2D TEE and the RT-3D-FV dataset (Qlab) were performed offline by two independent examiners.\backslashr\backslashnRESULTS\backslashr\backslashnAfter approval by the local ethic committee and obtaining written informed consent 50 patients (31 male and 19 female) with a mean age of 59.4 \pm 11.5 years were enrolled in this study. All measurements recommended for chamber and valve quantification could be performed on the basis of the RT-3D-FV data set except for measurements of the sinus of Valsalva and the sinotubular junction. There was good correlation between the results of the two methods.\backslashr\backslashnCONCLUSIONS\backslashr\backslashnFor intraoperative problem focussed TEE examinations the acquisition of an additional RT-3D-FV TEE data set allows accurate measurement of most of the recommended chamber and valve quantification parameters.

Authors: A. Ender, S. Eibel, E. Hasheminejad, Markus Scholz, Udo X. Kaisers, Chirojit Mukherjee, Joerg Ender

Date Published: 1st Oct 2012

Publication Type: Journal article

A new evaluation and training system for micro-telemanipulation at the middle ear
Genetical Statistics and Systems Biology

Abstract (Expand)

In this article, a new surgical model for evaluating telemanipulators used in middle ear surgery is presented. The purpose of this work was to develop an evaluation and training system which imitates … a typical surgical task of middle ear surgery and which can easily be repeated in order to get significant result. The abstract task can be performed manually or by means of a microsurgical telemanipulator and guaranties stable experimental conditions between different subjects at any time. As a task the stapedotomy was chosen, due to the high demands in positioning and in applying forces to the delicate structures in the middle ear. The manual and telemanipulated performance of 15 ENT surgeons and 17 medical students was compared using this evaluation and training system. In this article, a new surgical model for evaluating telemanipulators used in middle ear surgery is presented. The purpose of this work was to develop an evaluation and training system which imitates a typical surgical task of middle ear surgery and which can easily be repeated in order to get significant result. The abstract task can be performed manually or by means of a microsurgical telemanipulator and guaranties stable experimental conditions between different subjects at any time. As a task the stapedotomy was chosen, due to the high demands in positioning and in applying forces to the delicate structures in the middle ear. The manual and telemanipulated performance of 15 ENT surgeons and 17 medical students was compared using this evaluation and training system.

Authors: Thomas Maier, Gero Strauss, Markus Scholz, Thomas Berger, Anne Kielhorn, Konrad Entsfellner, Christian Willim, Wolfgang Buscher, Andreas Dietz, Tim C. Lueth

Date Published: 1st Aug 2012

Publication Type: Journal article

KMWin--a convenient tool for graphical presentation of results from Kaplan-Meier survival time analysis.
GLA - German Lymphoma Alliance, Genetical Statistics and Systems Biology

Abstract (Expand)

BACKGROUND: Analysis of clinical studies often necessitates multiple graphical representations of the results. Many professional software packages are available for this purpose. Most packages are … either only commercially available or hard to use especially if one aims to generate or customize a huge number of similar graphical outputs. We developed a new, freely available software tool called KMWin (Kaplan-Meier for Windows) facilitating Kaplan-Meier survival time analysis. KMWin is based on the statistical software environment R and provides an easy to use graphical interface. Survival time data can be supplied as SPSS (sav), SAS export (xpt) or text file (dat), which is also a common export format of other applications such as Excel. Figures can directly be exported in any graphical file format supported by R. RESULTS: On the basis of a working example, we demonstrate how to use KMWin and present its main functions. We show how to control the interface, customize the graphical output, and analyse survival time data. A number of comparisons are performed between KMWin and SPSS regarding graphical output, statistical output, data management and development. Although the general functionality of SPSS is larger, KMWin comprises a number of features useful for survival time analysis in clinical trials and other applications. These are for example number of cases and number of cases under risk within the figure or provision of a queue system for repetitive analyses of updated data sets. Moreover, major adjustments of graphical settings can be performed easily on a single window. CONCLUSIONS: We conclude that our tool is well suited and convenient for repetitive analyses of survival time data. It can be used by non-statisticians and provides often used functions as well as functions which are not supplied by standard software packages. The software is routinely applied in several clinical study groups.

Authors: A. Gross, M. Ziepert, M. Scholz

Date Published: 23rd Jun 2012

Publication Type: Not specified

Combined effects of different interleukin-28B gene variants on the outcome of dual combination therapy in chronic hepatitis C virus type 1 infection
Genetical Statistics and Systems Biology

Abstract (Expand)

In patients with chronic hepatitis C virus (HCV) infection, several variants of the interleukin-28B (IL28B) gene have been shown to correlate significantly with a sustained virologic response (SVR). … Recent evidence shows that determination of one single IL28B polymorphism, rs12979860, is sufficient for predicting treatment outcome. We examined whether the combined determination of the IL28B single-nucleotide polymorphisms (SNPs), rs12979860, rs8099917, rs12980275, and rs8103142, might improve the prediction of SVR in patients with HCV. In the study cohort, 54% of 942 patients with chronic HCV type 1 infection had SVR. The IL28B SNPs, rs12979860CC and rs8099917TT, correlated significantly with SVR (68% and 62%). The SNPs, rs12980275 and rs8103142, were in strong linkage disequilibrium with rs12979860 and were not included in further analysis. In homozygous carriers of the rs12979860 responder allele C, additional genotyping of the rs8099917 SNP had no effect on response prediction, whereas in carriers of the rs12979860 nonresponder allele, the rs8099917 SNP improved the response prediction. In heterozygous carriers of the rs12979860 nonresponder T allele, SVR rates were 55% in the presence of the rs8099917TT genotype and 40% in patients carrying the rs8099917 TG or GG genotype. Analysis of an independent confirmation cohort of 377 HCV type 1-infected patients verified the significant difference in SVR rates between the combined genotypes, rs12979860CT/rs8099917TT and rs12979860CT/rs8099917TG (38% versus 21%; P = 0.018). Conclusion: Treatment outcome prediction could not be improved in homozygous carriers of the IL28B rs12979860 C responder allele by the additional determination of the rs8099917 SNP. There is evidence that a significant proportion of heterozygous carriers of the rs12979860 T nonresponder allele can profit with respect to SVR prediction by further determination of the rs8099917 SNP. (HEPATOLOGY 2012;55:1700-1710).

Authors: Janett Fischer, Stephan Böhm, Markus Scholz, Tobias Müller, Heiko Witt, Jacob George, Christoph Sarrazin, Simone Susser, Eckart Schott, Vijayaprakash Suppiah, David R. Booth, Graeme J. Stewart, Florian van Bömmel, Annika Brodzinski, Balazs Fülöp, Pascal Migaud, Thomas Berg

Date Published: 1st Jun 2012

Publication Type: Journal article

Pre-operative Tei Index does not predict left ventricular function immediately after mitral valve repair
Genetical Statistics and Systems Biology

Abstract (Expand)

Echocardiographic assessment of systolic left ventricular (LV) function in patients with severe mitral regurgitation (MR) undergoing mitral valve (MV) repair can be challenging because the measurement … of ejection fraction (EF) or fractional area change (FAC) in pathological states is of questionable value. The aim of our study was to evaluate the usefulness of the pre-operative Tei Index in predicting left ventricular EF or FAC immediately after MV repair. One hundred and thirty patients undergoing MV repair with sinus rhythm pre- and post-operatively were enrolled in this prospective study. Twenty-six patients were excluded due to absence of sinus rhythm post-operatively. Standard transesophageal examination (IE 33, Philips, Netherlands) was performed before and after cardiopulmonary bypass according to the guidelines of the ASE/SCA. FAC was determined in the transgastric midpapillary short-axis view. LV EF was measured in the midesophageal four- and two-chamber view. For calculation of the Tei Index, the deep transgastric and the midesophageal four-chamber view were used. Statistical analysis was performed with SPSS 17.0. values are expressed as mean with standard deviation. LV FAC and EF decreased significantly after MV repair (FAC: 56\pm12% vs. 50\pm14%, P\textless0.001; EF: 58\pm11 vs. 50\pm12\textgreek’E P\textless0.001). The Tei Index decreased from 0.66\pm0.23 before MV repair to 0.41\pm0.19 afterwards (P\textless0.001). No relationship between pre-operative Tei Index and post-operative FAC or post-operative EF were found (FAC: r=-0.061, P=0.554; EF: r=-0.29, P=0.771). Conclusion: Pre-operative Tei Index is not a good predictor for post-operative FAC and EF in patients undergoing MV repair.

Authors: Chirojit Mukherjee, Steffen Groeger, Maurice Hogan, Markus Scholz, Udo X. Kaisers, Joerg Ender

Date Published: 2012

Publication Type: Journal article

Intrathecal morphine is superior to intravenous PCA in patients undergoing minimally invasive cardiac surgery
Genetical Statistics and Systems Biology

Abstract (Expand)

Aim of our study was to evaluate the beneficial effect of low dose intrathecal morphine on postoperative analgesia, over the use of intravenous patient controlled anesthesia (PCA), in patients undergoing … fast track anesthesia during minimally invasive cardiac surgical procedures. A randomized controlled trial was undertaken after approval from local ethical committee. Written informed consent was obtained from 61 patients receiving mitral or tricuspid or both surgical valve repair in minimal invasive technique. Patients were assigned randomly to 2 groups. Group 1 received general anesthesia and intravenous patient controlled analgesia (PCA) pump with Piritramide (GA group). Group 2 received a single shot of intrathecal morphine (1.5 \textgreekmg/kg body weight) prior to the administration of general anesthesia (ITM group). Site of puncture was confined to lumbar (L1-2 or L2-3) intrathecal space. The amount of intravenous piritramide used in post anesthesia care unit (PACU) and the first postoperative day was defined as primary end point. Secondary end points included: time for tracheal extubation, pain and sedation scores in PACU upto third postoperative day. For statistical analysis Mann-Whitney-U Test and Fishers exact test (SPSS) were used. We found that the demand for intravenous opioids in PACU was significantly reduced in ITM group (P \textless0.001). Pain scores were significantly decreased in ITM group until second postoperative day (P \textless0.01). There was no time delay for tracheal extubation in ITM group, and sedation scores did not differ in either group. We conclude that low dose single shot intrathecal morphine provides adequate postoperative analgesia, reduces the intravenous opioid consumption during the early postoperative period and does not defer early extubation.

Authors: Chirojit Mukherjee, Eva Koch, Joergen Banusch, Markus Scholz, Udo X. Kaisers, Joerg Ender

Date Published: 2012

Publication Type: Journal article

Biomathematische Modellierung von Therapiewirkungen bei Lymphomerkrankungen - Ein Beitrag zur Medizinischen Systembiologie
Genetical Statistics and Systems Biology

Abstract

Not specified

Author: Markus Scholz

Date Published: 2012

Publication Type: Journal article

Rationale and design of the Leipzig (LIFE) Heart Study: phenotyping and cardiovascular characteristics of patients with coronary artery disease
Genetical Statistics and Systems Biology

Abstract (Expand)

OBJECTIVE\backslashr\backslashnWe established the Leipzig (LIFE) Heart Study, a biobank and database of patients with different stages of coronary artery disease (CAD) for studies of clinical, metabolic, … cellular and genetic factors of cardiovascular diseases.\backslashr\backslashnDESIGN\backslashr\backslashnThe Leipzig (LIFE) Heart Study (NCT00497887) is an ongoing observational angiographic study including subjects with different entities of CAD. Cohort 1, patients undergoing first-time diagnostic coronary angiography due to suspected stable CAD with previously untreated coronary arteries. Cohort 2, patients with acute myocardial infarction (MI) requiring percutaneous revascularization. Cohort 3, patients with known left main coronary artery disease (LMCAD).\backslashr\backslashnRESULTS\backslashr\backslashnWe present preliminary results of demographics and phenotyping based on a 4-years analysis of a total of 3,165 subjects. Cohort 1 (n=2,274) shows the typical distribution of elective coronary angiography cohorts with 43% cases with obstructive CAD and 37% normal angiograms. Cohorts 2 and 3 consist of 590 and 301 subjects, respectively, adding patients with severe forms of CAD. The suitability of the database and biobank to perform association studies was confirmed by replication of the CAD susceptibility locus on chromosome 9p21 (OR per allele: 1.55 (any CAD), 1.54 (MI), 1.74 (LMCAD), p\textless10(-6), respectively). A novel finding was that patients with LMCAD had a stronger association with 9p21 than patients with obstructive CAD without LMCAD (OR 1.22, p=0.042). In contrast, 9p21 did not associate with myocardial infarction in excess of stable CAD.\backslashr\backslashnCONCLUSION\backslashr\backslashnThe Leipzig (LIFE) Heart Study provides a basis to identify molecular targets related to atherogenesis and associated metabolic disorders. The study may contribute to an improvement of individual prediction, prevention, and treatment of CAD. OBJECTIVE We established the Leipzig (LIFE) Heart Study, a biobank and database of patients with different stages of coronary artery disease (CAD) for studies of clinical, metabolic, cellular and genetic factors of cardiovascular diseases. DESIGN The Leipzig (LIFE) Heart Study (NCT00497887) is an ongoing observational angiographic study including subjects with different entities of CAD. Cohort 1, patients undergoing first-time diagnostic coronary angiography due to suspected stable CAD with previously untreated coronary arteries. Cohort 2, patients with acute myocardial infarction (MI) requiring percutaneous revascularization. Cohort 3, patients with known left main coronary artery disease (LMCAD). RESULTS We present preliminary results of demographics and phenotyping based on a 4-years analysis of a total of 3,165 subjects. Cohort 1 (n=2,274) shows the typical distribution of elective coronary angiography cohorts with 43% cases with obstructive CAD and 37% normal angiograms. Cohorts 2 and 3 consist of 590 and 301 subjects, respectively, adding patients with severe forms of CAD. The suitability of the database and biobank to perform association studies was confirmed by replication of the CAD susceptibility locus on chromosome 9p21 (OR per allele: 1.55 (any CAD), 1.54 (MI), 1.74 (LMCAD), p\textless10(-6), respectively). A novel finding was that patients with LMCAD had a stronger association with 9p21 than patients with obstructive CAD without LMCAD (OR 1.22, p=0.042). In contrast, 9p21 did not associate with myocardial infarction in excess of stable CAD. CONCLUSION The Leipzig (LIFE) Heart Study provides a basis to identify molecular targets related to atherogenesis and associated metabolic disorders. The study may contribute to an improvement of individual prediction, prevention, and treatment of CAD. OBJECTIVE We established the Leipzig (LIFE) Heart Study, a biobank and database of patients with different stages of coronary artery disease (CAD) for studies of clinical, metabolic, cellular and genetic factors of cardiovascular diseases. DESIGN The Leipzig (LIFE) Heart Study (NCT00497887) is an ongoing observational angiographic study including subjects with different entities of CAD. Cohort 1, patients undergoing first-time diagnostic coronary angiography due to suspected stable CAD with previously untreated coronary arteries. Cohort 2, patients with acute myocardial infarction (MI) requiring percutaneous revascularization. Cohort 3, patients with known left main coronary artery disease (LMCAD). RESULTS We present preliminary results of demographics and phenotyping based on a 4-years analysis of a total of 3,165 subjects. Cohort 1 (n=2,274) shows the typical distribution of elective coronary angiography cohorts with 43% cases with obstructive CAD and 37% normal angiograms. Cohorts 2 and 3 consist of 590 and 301 subjects, respectively, adding patients with severe forms of CAD. The suitability of the database and biobank to perform association studies was confirmed by replication of the CAD susceptibility locus on chromosome 9p21 (OR per allele: 1.55 (any CAD), 1.54 (MI), 1.74 (LMCAD), p\textless10(-6), respectively). A novel finding was that patients with LMCAD had a stronger association with 9p21 than patients with obstructive CAD without LMCAD (OR 1.22, p=0.042). In contrast, 9p21 did not associate with myocardial infarction in excess of stable CAD. CONCLUSION The Leipzig (LIFE) Heart Study provides a basis to identify molecular targets related to atherogenesis and associated metabolic disorders. The study may contribute to an improvement of individual prediction, prevention, and treatment of CAD. OBJECTIVE We established the Leipzig (LIFE) Heart Study, a biobank and database of patients with different stages of coronary artery disease (CAD) for studies of clinical, metabolic, cellular and genetic factors of cardiovascular diseases. DESIGN The Leipzig (LIFE) Heart Study (NCT00497887) is an ongoing observational angiographic study including subjects with different entities of CAD. Cohort 1, patients undergoing first-time diagnostic coronary angiography due to suspected stable CAD with previously untreated coronary arteries. Cohort 2, patients with acute myocardial infarction (MI) requiring percutaneous revascularization. Cohort 3, patients with known left main coronary artery disease (LMCAD). RESULTS We present preliminary results of demographics and phenotyping based on a 4-years analysis of a total of 3,165 subjects. Cohort 1 (n=2,274) shows the typical distribution of elective coronary angiography cohorts with 43% cases with obstructive CAD and 37% normal angiograms. Cohorts 2 and 3 consist of 590 and 301 subjects, respectively, adding patients with severe forms of CAD. The suitability of the database and biobank to perform association studies was confirmed by replication of the CAD susceptibility locus on chromosome 9p21 (OR per allele: 1.55 (any CAD), 1.54 (MI), 1.74 (LMCAD), p\textless10(-6), respectively). A novel finding was that patients with LMCAD had a stronger association with 9p21 than patients with obstructive CAD without LMCAD (OR 1.22, p=0.042). In contrast, 9p21 did not associate with myocardial infarction in excess of stable CAD. CONCLUSION The Leipzig (LIFE) Heart Study provides a basis to identify molecular targets related to atherogenesis and associated metabolic disorders. The study may contribute to an improvement of individual prediction, prevention, and treatment of CAD. OBJECTIVE We established the Leipzig (LIFE) Heart Study, a biobank and database of patients with different stages of coronary artery disease (CAD) for studies of clinical, metabolic, cellular and genetic factors of cardiovascular diseases. DESIGN The Leipzig (LIFE) Heart Study (NCT00497887) is an ongoing observational angiographic study including subjects with different entities of CAD. Cohort 1, patients undergoing first-time diagnostic coronary angiography due to suspected stable CAD with previously untreated coronary arteries. Cohort 2, patients with acute myocardial infarction (MI) requiring percutaneous revascularization. Cohort 3, patients with known left main coronary artery disease (LMCAD). RESULTS We present preliminary results of demographics and phenotyping based on a 4-years analysis of a total of 3,165 subjects. Cohort 1 (n=2,274) shows the typical distribution of elective coronary angiography cohorts with 43% cases with obstructive CAD and 37% normal angiograms. Cohorts 2 and 3 consist of 590 and 301 subjects, respectively, adding patients with severe forms of CAD. The suitability of the database and biobank to perform association studies was confirmed by replication of the CAD susceptibility locus on chromosome 9p21 (OR per allele: 1.55 (any CAD), 1.54 (MI), 1.74 (LMCAD), p\textless10(-6), respectively). A novel finding was that patients with LMCAD had a stronger association with 9p21 than patients with obstructive CAD without LMCAD (OR 1.22, p=0.042). In contrast, 9p21 did not associate with myocardial infarction in excess of stable CAD. CONCLUSION The Leipzig (LIFE) Heart Study provides a basis to identify molecular targets related to atherogenesis and associated metabolic disorders. The study may contribute to an improvement of individual prediction, prevention, and treatment of CAD.

Authors: Frank Beutner, Daniel Teupser, Stephan Gielen, Lesca Miriam Holdt, Markus Scholz, Enno Boudriot, Gerhard Schuler, Joachim Thiery, Massimo Federici

Date Published: 22nd Dec 2011

Publication Type: Journal article

Comparison of scoring methods for the detection of causal genes with or without rare variants
Genetical Statistics and Systems Biology

Abstract (Expand)

Rare causal variants are believed to significantly contribute to the genetic basis of common diseases or quantitative traits. Appropriate statistical methods are required to discover the highest possible … number of disease-relevant variants in a genome-wide screening study. The publicly available Genetic Analysis Workshop 17 data set consists of 697 individuals and 24,487 genetic variants. It includes a simulated complex disease model with intermediate quantitative phenotypes. We compare four gene-wise scoring methods with respect to ranking of causal genes under variable allele frequency thresholds for collapsing of rare variants and considering whether or not rare variants were included. We also compare causal genes for which the ranks differ clearly between scoring methods regarding such characteristics as number and strength of causal variants. We corroborated our findings with additional simulations. We found that the maximum statistics method was superior in assigning high ranks to genes with a single strong causal variant. Hotelling’s T2 test was superior for genes with several independent causal variants. This was consistent for all phenotypes and was confirmed by single-gene analyses and additional simulations. The multivariate analysis performed similarly to Hotelling’s T2 test. The least absolute shrinkage and selection operator (LASSO) analysis was widely comparable with the maximum statistics method. We conclude that the maximum statistics method is a superior alternative to Hotelling’s T2 test if one expects only one independent causal variant per gene with a dominating effect. Such a variant could also be a supermarker derived by collapsing rare variants. Because the true nature of the genetic effect is unknown for real data, both methods need to be taken into consideration.

Authors: Markus Scholz, Holger Kirsten

Date Published: 1st Dec 2011

Publication Type: Journal article

High resolution genomic profiling and classical cytogenetics in a group of benign and atypical meningiomas
Genetical Statistics and Systems Biology

Abstract (Expand)

Meningiomas are classified as benign, atypical, or anaplastic. The majority are sporadic, solitary, and benign tumors with favorable prognoses. However, the prognosis for patients with anaplastic … meningiomas remains less favorable. High resolution genomic profiling has the capacity to provide more detailed information. Therefore, we analyzed genomic aberrations of benign and atypical meningiomas using single nucleotide polymorphism (SNP) array, combined with G-banding by trypsin using Giemsa stain (GTG banding), spectral karyotyping, and locus-specific fluorescence in situ hybridization (FISH). We confirmed frequently detected chromosomal aberrations in meningiomas and identified novel genetic events. Applying SNP array, we identified constitutional de novo loss or gain within chromosome 22 in three patients, possibly representing inherited causal events for meningioma formation. We show evidence for somatic segmental uniparental disomy in regions 4p16.1, 7q31.2, 8p23.2, and 9p22.1 not previously described for primary meningioma. GTG-banding and spectral karyotyping detected a novel balanced reciprocal translocation t(4;10)(q12;q26) in one benign meningioma. A paracentric inversion within 1p36, previously described as novel, was detected as a recurrent chromosomal aberration in benign and atypical meningiomas. Analyses of tumors and matched normal tissues with a combination of SNP arrays and complementary techniques will help to further elucidate potentially causal genetic events for tumorigenesis of meningioma.

Authors: Heidrun Holland, Kristin Mocker, Peter Ahnert, Holger Kirsten, Helene Hantmann, Ronald Koschny, Manfred Bauer, Ralf Schober, Markus Scholz, Jürgen Meixensberger, Wolfgang Krupp

Date Published: 1st Oct 2011

Publication Type: Journal article

Genetic variation in the Sorbs of eastern Germany in the context of broader European genetic diversity
Genetical Statistics and Systems Biology

Abstract (Expand)

Population isolates have long been of interest to genetic epidemiologists because of their potential to increase power to detect disease-causing genetic variants. The Sorbs of Germany are considered … as cultural and linguistic isolates and have recently been the focus of disease association mapping efforts. They are thought to have settled in their present location in eastern Germany after a westward migration from a largely Slavic-speaking territory during the Middle Ages. To examine Sorbian genetic diversity within the context of other European populations, we analyzed genotype data for over 30 000 autosomal single-nucleotide polymorphisms from over 200 Sorbs individuals. We compare the Sorbs with other European individuals, including samples from population isolates. Despite their geographical proximity to German speakers, the Sorbs showed greatest genetic similarity to Polish and Czech individuals, consistent with the linguistic proximity of Sorbian to other West Slavic languages. The Sorbs also showed evidence of subtle levels of genetic isolation in comparison with samples from non-isolated European populations. The level of genetic isolation was less than that observed for the Sardinians and French Basque, who were clear outliers on multiple measures of isolation. The finding of the Sorbs as only a minor genetic isolate demonstrates the need to genetically characterize putative population isolates, as they possess a wide range of levels of isolation because of their different demographic histories.

Authors: Krishna R. Veeramah, Anke Tönjes, Peter Kovacs, Arnd Gross, Daniel Wegmann, Patrick Geary, Daniela Gasperikova, Iwar Klimes, Markus Scholz, John Novembre, Michael Stumvoll

Date Published: 1st Sep 2011

Publication Type: Journal article

Circulating Nampt and RBP4 levels in patients with carotid stenosis undergoing carotid endarterectomy (CEA)
Genetical Statistics and Systems Biology

Abstract (Expand)

BACKGROUND\backslashr\backslashnObesity is a risk factor for atherosclerotic vascular disease. Altered adipokine secretion, including increased production of nicotinamide phosphoribosyltransferase … (Nampt) and retinol binding protein 4 (RBP4) may link adipose tissue dysfunction to cardiovascular complications.\backslashr\backslashnMETHODS\backslashr\backslashnWe determined Nampt and RBP4 serum concentrations in 193 consecutive patients with carotid stenosis prior to carotid endarterectomy (CEA) in relation to recently experienced ischemic events, markers of atherosclerosis and obesity, as well as anthropometric and clinical characteristics.\backslashr\backslashnRESULTS\backslashr\backslashnNampt but not RBP4 was significantly higher in symptomatic patients who experienced an ischemic event within 6 months before surgery compared to asymptomatic patients (p=0.001). In multivariate regression analysis Nampt was the only independent predictor of symptomatic carotid stenosis. Nampt correlated with peripheral leukocyte blood count (p\textless0.0001) and with the number of macrophages/foam cells within carotid plaques (p=0.042). However, Nampt and RBP4 serum concentrations did not correlate with the maximum percentage of carotid stenosis.\backslashr\backslashnCONCLUSION\backslashr\backslashnOur data suggest circulating Nampt as an independent predictor of recently experienced ischemic events in patients with carotid stenosis despite the lack of an association between Nampt and carotid atherosclerosis severity. BACKGROUND Obesity is a risk factor for atherosclerotic vascular disease. Altered adipokine secretion, including increased production of nicotinamide phosphoribosyltransferase (Nampt) and retinol binding protein 4 (RBP4) may link adipose tissue dysfunction to cardiovascular complications. METHODS We determined Nampt and RBP4 serum concentrations in 193 consecutive patients with carotid stenosis prior to carotid endarterectomy (CEA) in relation to recently experienced ischemic events, markers of atherosclerosis and obesity, as well as anthropometric and clinical characteristics. RESULTS Nampt but not RBP4 was significantly higher in symptomatic patients who experienced an ischemic event within 6 months before surgery compared to asymptomatic patients (p=0.001). In multivariate regression analysis Nampt was the only independent predictor of symptomatic carotid stenosis. Nampt correlated with peripheral leukocyte blood count (p\textless0.0001) and with the number of macrophages/foam cells within carotid plaques (p=0.042). However, Nampt and RBP4 serum concentrations did not correlate with the maximum percentage of carotid stenosis. CONCLUSION Our data suggest circulating Nampt as an independent predictor of recently experienced ischemic events in patients with carotid stenosis despite the lack of an association between Nampt and carotid atherosclerosis severity.

Authors: Gabriela Aust, Migle Uptaite-Patapoviene, Markus Scholz, Olaf Richter, Silvio Rohm, Matthias Blüher

Date Published: 1st Jun 2011

Publication Type: Journal article

Increased CD64 expression on polymorphonuclear neutrophils indicates infectious complications following solid organ transplantation
Genetical Statistics and Systems Biology

Abstract (Expand)

The aim of this study was to evaluate the diagnostic value of monitoring CD64 antigen upregulation on polymorphonuclear neutrophils (PMN) for the identification of infectious complications in the … postoperative course of solid organ transplanted patients. Twenty-five kidney, 13 liver, and four pancreas-kidney transplanted patients were included. Beginning with preoperative values up to postoperative values after 3 months for each patient, the PMN CD64 Index, HLA-DR on monocytes, NKp44+ NK and NK/T cells, CXCR3+ NK cells, CXCR3+ T helper cells, CXCR3+ NK/T cells, and CD4/CD8 ratio were measured by flow cytometry. Subsequently they were correlated with confirmed postoperative complications. Measuring the PMN CD64 Index reached a sensitivity of 89% and a specificity of 65% in the detection of infectious complications. Concerning this matter, it was a significantly better marker than all other included parameters except CXCR3+ NK/T cells. In contrast, according to our results the PMN CD64 Index has no diagnostic relevance in detection of rejections. The combination of included parameters showed no improved diagnostic value. Due to its high sensitivity and specificity for infectious complications CD64 on PMN could be proven a very good indicator in evaluating suspected infectious complications in the postoperative course of transplanted patients. The aim of this study was to evaluate the diagnostic value of monitoring CD64 antigen upregulation on polymorphonuclear neutrophils (PMN) for the identification of infectious complications in the postoperative course of solid organ transplanted patients. Twenty-five kidney, 13 liver, and four pancreas-kidney transplanted patients were included. Beginning with preoperative values up to postoperative values after 3 months for each patient, the PMN CD64 Index, HLA-DR on monocytes, NKp44+ NK and NK/T cells, CXCR3+ NK cells, CXCR3+ T helper cells, CXCR3+ NK/T cells, and CD4/CD8 ratio were measured by flow cytometry. Subsequently they were correlated with confirmed postoperative complications. Measuring the PMN CD64 Index reached a sensitivity of 89% and a specificity of 65% in the detection of infectious complications. Concerning this matter, it was a significantly better marker than all other included parameters except CXCR3+ NK/T cells. In contrast, according to our results the PMN CD64 Index has no diagnostic relevance in detection of rejections. The combination of included parameters showed no improved diagnostic value. Due to its high sensitivity and specificity for infectious complications CD64 on PMN could be proven a very good indicator in evaluating suspected infectious complications in the postoperative course of transplanted patients.

Authors: Daniel Grey, Ulrich Sack, Markus Scholz, Heike Knaack, Stephan Fricke, Christoph Oppel, Daniel Luderer, Josef Fangmann, Frank Emmrich, Manja Kamprad

Date Published: 1st Jun 2011

Publication Type: Journal article

Influence of low dose irradiation on differentiation, maturation and T-cell activation of human dendritic cells
Genetical Statistics and Systems Biology

Abstract (Expand)

Ionizing irradiation could act directly on immune cells and may induce bystander effects mediated by soluble factors that are released by the irradiated cells. This is the first study analyzing both … the direct effect of low dose ionizing radiation (LDIR) on the maturation and cytokine release of human dendritic cells (DCs) and the functional consequences for co-cultured T-cells. We showed that irradiation of DC-precursors in vitro does not influence surface marker expression or cytokine profile of immature DCs nor of mature DCs after LPS treatment. There was no difference of single dose irradiation versus fractionated irradiation protocols on the behavior of the mature DCs. Further, the low dose irradiation did not change the capacity of the DCs to stimulate T-cell proliferation. But the irradiation of the co-culture of DCs and T-cells revealed significantly lower proliferation of T-cells with higher doses. Summarizing the data from approx. 50 DC preparations there is no significant effect of low dose ionizing irradiation on the cytokine profile, surface marker expression and maturation of DCs in vitro although functional consequences cannot be excluded. Ionizing irradiation could act directly on immune cells and may induce bystander effects mediated by soluble factors that are released by the irradiated cells. This is the first study analyzing both the direct effect of low dose ionizing radiation (LDIR) on the maturation and cytokine release of human dendritic cells (DCs) and the functional consequences for co-cultured T-cells. We showed that irradiation of DC-precursors in vitro does not influence surface marker expression or cytokine profile of immature DCs nor of mature DCs after LPS treatment. There was no difference of single dose irradiation versus fractionated irradiation protocols on the behavior of the mature DCs. Further, the low dose irradiation did not change the capacity of the DCs to stimulate T-cell proliferation. But the irradiation of the co-culture of DCs and T-cells revealed significantly lower proliferation of T-cells with higher doses. Summarizing the data from approx. 50 DC preparations there is no significant effect of low dose ionizing irradiation on the cytokine profile, surface marker expression and maturation of DCs in vitro although functional consequences cannot be excluded.

Authors: Jutta Jahns, Ulf Anderegg, Anja Saalbach, Britt Rosin, Ina Patties, Annegret Glasow, Manja Kamprad, Markus Scholz, Guido Hildebrandt

Date Published: 1st May 2011

Publication Type: Journal article

Monitoring of WT1 expression in PB and CD34(+) donor chimerism of BM predicts early relapse in AML and MDS patients after hematopoietic cell transplantation with reduced-intensity conditioning
Genetical Statistics and Systems Biology

Abstract (Expand)

Relapse of malignant disease remains the major complication in patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) after hematopoietic cell transplantation (HCT) with … reduced-intensity conditioning (RIC). In this study, we investigated the predictive value of disease-specific markers (DSMs), donor chimerism (DC) analysis of unsorted (UDC) or CD34(+) sorted cells and Wilms’ tumor gene 1 (WT1) expression. Eighty-eight patients with AML or MDS were monitored after allogenic HCT following 2 Gy total-body irradiation with (n=84) or without (n=4) fludarabine 3 \times 30 mg/m(2), followed by cyclosporin A and mycophenolate mofetil. DSMs were determined by fluorescence in situ hybridization (FISH) and WT1 expression by real-time polymerase chain reaction. Chimerism analysis was performed on unsorted or CD34(+) sorted cells, by FISH or short tandem repeat polymerase chain reaction. Twenty-one (24%) patients relapsed within 4 months after HCT. UDC, CD34(+) DC and WT1 expression were each significant predictors of relapse with sensitivities ranging from 53 to 79% and specificities of 82-91%. Relapse within 28 days was excluded almost entirely on the basis of WT1 expression combined with CD34(+) DC kinetics. Monitoring of WT1 expression and CD34(+) DC predict relapse of AML and MDS after RIC-HCT.

Authors: T. Lange, M. Hubmann, Ralph Burkhardt, G-N Franke, M. Cross, Markus Scholz, S. Leiblein, H. K. Al-Ali, J. Edelmann, Joachim Thiery, D. Niederwieser

Date Published: 1st Mar 2011

Publication Type: Journal article

Impact of first- and second-line treatment for Hodgkin’s lymphoma on the incidence of AML/MDS and NHL–experience of the German Hodgkin’s Lymphoma Study Group analyzed by a parametric model of carcinogenesis
Genetical Statistics and Systems Biology

Abstract (Expand)

BACKGROUND\backslashr\backslashnUsing a parametric carcinogenesis model, we disentangle the superimposing effects of primary and relapse therapies of Hodgkin’s disease on secondary … neoplasias.\backslashr\backslashnPATIENTS AND METHODS\backslashr\backslashnWe analyze eight randomized trials of the German Hodgkin’s lymphoma study group [5357 individuals, 67 secondary acute myeloid leukemia (AML)/myelodysplastic syndrome (MDS) and 97 secondary non-Hodgkin’s lymphoma (NHL)]. Primary therapies were divided into four groups: radiotherapy alone, moderately dosed COPP/ABVD-like chemotherapies for intermediate and advanced stages and BEACOPP escalated.\backslashr\backslashnRESULTS\backslashr\backslashnFor secondary AML/MDS, the hazards after primary therapies are proportional (maximum at 3.4 years), while the hazard after relapse therapy is more peaked (maximum at 1.8 years). Intermediate and advanced stage chemotherapy resulted in a cumulative risk of 1.5%, while the risk after BEACOPP escalated is higher (4.4%, P = 0.004) and comparable with that after relapse therapy (4.5%). For secondary NHL, there are no differences in cumulative risk between the primary therapies (2.9%), while the risk after relapse therapy is increased (6.6%, P = 0.002).\backslashr\backslashnCONCLUSIONS\backslashr\backslashnBEACOPP escalated moderately increases the risk of secondary AML/MDS but not NHL. No differences were found between other chemotherapies of advanced stages and intermediate stages. Secondary AML/MDS occurs faster after relapse treatment than after primary treatment.

Authors: Markus Scholz, A. Engert, J. Franklin, A. Josting, V. Diehl, Dirk Hasenclever, Markus Loeffler

Date Published: 1st Mar 2011

Publication Type: Journal article

Population-genetic comparison of the Sorbian isolate population in Germany with the German KORA population using genome-wide SNP arrays
Genetical Statistics and Systems Biology

Abstract (Expand)

BACKGROUND\backslashr\backslashnThe Sorbs are an ethnic minority in Germany with putative genetic isolation, making the population interesting for disease mapping. A sample of N = 977 Sorbs is currently … analysed in several genome-wide meta-analyses. Since genetic differences between populations are a major confounding factor in genetic meta-analyses, we compare the Sorbs with the German outbred population of the KORA F3 study (N = 1644) and other publically available European HapMap populations by population genetic means. We also aim to separate effects of over-sampling of families in the Sorbs sample from effects of genetic isolation and compare the power of genetic association studies between the samples.\backslashr\backslashnRESULTS\backslashr\backslashnThe degree of relatedness was significantly higher in the Sorbs. Principal components analysis revealed a west to east clustering of KORA individuals born in Germany, KORA individuals born in Poland or Czech Republic, Half-Sorbs (less than four Sorbian grandparents) and Full-Sorbs. The Sorbs cluster is nearest to the cluster of KORA individuals born in Poland. The number of rare SNPs is significantly higher in the Sorbs sample. FST between KORA and Sorbs is an order of magnitude higher than between different regions in Germany. Compared to the other populations, Sorbs show a higher proportion of individuals with runs of homozygosity between 2.5 Mb and 5 Mb. Linkage disequilibrium (LD) at longer range is also slightly increased but this has no effect on the power of association studies. Oversampling of families in the Sorbs sample causes detectable bias regarding higher FST values and higher LD but the effect is an order of magnitude smaller than the observed differences between KORA and Sorbs. Relatedness in the Sorbs also influenced the power of uncorrected association analyses.\backslashr\backslashnCONCLUSIONS\backslashr\backslashnSorbs show signs of genetic isolation which cannot be explained by over-sampling of relatives, but the effects are moderate in size. The Slavonic origin of the Sorbs is still genetically detectable. Regarding LD structure, a clear advantage for genome-wide association studies cannot be deduced. The significant amount of cryptic relatedness in the Sorbs sample results in inflated variances of Beta-estimators which should be considered in genetic association analyses. BACKGROUND The Sorbs are an ethnic minority in Germany with putative genetic isolation, making the population interesting for disease mapping. A sample of N = 977 Sorbs is currently analysed in several genome-wide meta-analyses. Since genetic differences between populations are a major confounding factor in genetic meta-analyses, we compare the Sorbs with the German outbred population of the KORA F3 study (N = 1644) and other publically available European HapMap populations by population genetic means. We also aim to separate effects of over-sampling of families in the Sorbs sample from effects of genetic isolation and compare the power of genetic association studies between the samples. RESULTS The degree of relatedness was significantly higher in the Sorbs. Principal components analysis revealed a west to east clustering of KORA individuals born in Germany, KORA individuals born in Poland or Czech Republic, Half-Sorbs (less than four Sorbian grandparents) and Full-Sorbs. The Sorbs cluster is nearest to the cluster of KORA individuals born in Poland. The number of rare SNPs is significantly higher in the Sorbs sample. FST between KORA and Sorbs is an order of magnitude higher than between different regions in Germany. Compared to the other populations, Sorbs show a higher proportion of individuals with runs of homozygosity between 2.5 Mb and 5 Mb. Linkage disequilibrium (LD) at longer range is also slightly increased but this has no effect on the power of association studies. Oversampling of families in the Sorbs sample causes detectable bias regarding higher FST values and higher LD but the effect is an order of magnitude smaller than the observed differences between KORA and Sorbs. Relatedness in the Sorbs also influenced the power of uncorrected association analyses. CONCLUSIONS Sorbs show signs of genetic isolation which cannot be explained by over-sampling of relatives, but the effects are moderate in size. The Slavonic origin of the Sorbs is still genetically detectable. Regarding LD structure, a clear advantage for genome-wide association studies cannot be deduced. The significant amount of cryptic relatedness in the Sorbs sample results in inflated variances of Beta-estimators which should be considered in genetic association analyses. BACKGROUND The Sorbs are an ethnic minority in Germany with putative genetic isolation, making the population interesting for disease mapping. A sample of N = 977 Sorbs is currently analysed in several genome-wide meta-analyses. Since genetic differences between populations are a major confounding factor in genetic meta-analyses, we compare the Sorbs with the German outbred population of the KORA F3 study (N = 1644) and other publically available European HapMap populations by population genetic means. We also aim to separate effects of over-sampling of families in the Sorbs sample from effects of genetic isolation and compare the power of genetic association studies between the samples. RESULTS The degree of relatedness was significantly higher in the Sorbs. Principal components analysis revealed a west to east clustering of KORA individuals born in Germany, KORA individuals born in Poland or Czech Republic, Half-Sorbs (less than four Sorbian grandparents) and Full-Sorbs. The Sorbs cluster is nearest to the cluster of KORA individuals born in Poland. The number of rare SNPs is significantly higher in the Sorbs sample. FST between KORA and Sorbs is an order of magnitude higher than between different regions in Germany. Compared to the other populations, Sorbs show a higher proportion of individuals with runs of homozygosity between 2.5 Mb and 5 Mb. Linkage disequilibrium (LD) at longer range is also slightly increased but this has no effect on the power of association studies. Oversampling of families in the Sorbs sample causes detectable bias regarding higher FST values and higher LD but the effect is an order of magnitude smaller than the observed differences between KORA and Sorbs. Relatedness in the Sorbs also influenced the power of uncorrected association analyses. CONCLUSIONS Sorbs show signs of genetic isolation which cannot be explained by over-sampling of relatives, but the effects are moderate in size. The Slavonic origin of the Sorbs is still genetically detectable. Regarding LD structure, a clear advantage for genome-wide association studies cannot be deduced. The significant amount of cryptic relatedness in the Sorbs sample results in inflated variances of Beta-estimators which should be considered in genetic association analyses.

Authors: Arnd Gross, Anke Tönjes, Peter Kovacs, Krishna R. Veeramah, Peter Ahnert, Nab R. Roshyara, Christian Gieger, Ina-Maria Rueckert, Markus Loeffler, Mark Stoneking, Heinz-Erich Wichmann, John Novembre, Michael Stumvoll, Markus Scholz

Date Published: 2011

Publication Type: Journal article

Harmonization of growth hormone measurements with different immunoassays by data adjustment
Genetical Statistics and Systems Biology

Abstract (Expand)

BACKGROUND\backslashr\backslashnThe aim of our study was to evaluate the between-assay variability of commercially available immunoassays for the measurement of human growth hormone (hGH). In addition, … we asked whether the comparability of the diagnosis of childhood onset growth hormone deficiency could be improved by adjusting hGH results by statistical methods, such as linear regression, conversion factors, and quantile transformation.\backslashr\backslashnMETHODS\backslashr\backslashnIn archived sera from 312 children and adolescents (age: 17 days-17 years) hGH values between 0.01 and 16.5 ng/mL were determined by using the following immunoassays: AutoDELFIA (PerkinElmer), BC-IRMA (Beckman-Coulter), ELISA (Mediagnost), IMMULITE 2000 (Siemens), iSYS (IDS), Liaison (DiaSorin), UniCel DxI 800 Access (BeckmanCoulter) and {\textquotedblIn house{\textquotedbl-RIA (Tübingen).\backslashr\backslashnRESULTS\backslashr\backslashnThe assays differed in median hGH concentrations by as much as 5.44 ng/mL (Immulite), and as little as 2.67 ng/mL (BC-IRMA). The mean difference between assays ranged from 0.35 to 2.71 ng/mL, whereas several samples displayed differences up to 11.4 ng/mL. The best correlation (r=0.992) was found between AutoDELFIA and Liasion, the lowest (r=0.864) was between an in-house RIA and iSYS. The between-assay CV (mean \pm SD) of values within the cut-off range was 24.3% \pm 7.4%, resulting in an assay-dependent diagnosis of growth hormone deficiency (GHD) in more than 27% of patients. Yet, adjustment of this data by linear regression or a conversion factor reduced the CV below 14%, and the ratio of assay-dependent diagnoses below 8%. Using quantile transformation, the CV and ratio were reduced to 11.4% and \textless1%, respectively.\backslashr\backslashnCONCLUSIONS\backslashr\backslashnhGH measurements using different assays vary significantly. Linear regression, conversion factors, or particularly quantile transformation are useful tools to improve comparability in the diagnostic procedure for the confirmation of GHD in childhood and adolescence.

Authors: Anne Müller, Markus Scholz, Oliver Blankenstein, Gerhard Binder, Roland Pfäffle, Antje Körner, Wieland Kiess, Annegret Heider, Martin Bidlingmaier, Joachim Thiery, Jürgen Kratzsch

Date Published: 2011

Publication Type: Journal article

Spectral iEEG markers precede SSEP events during surgery for subarachnoid hemorrhage
Genetical Statistics and Systems Biology

Abstract (Expand)

OBJECTIVE\backslashr\backslashnDuring neurosurgical intracranial vascular manipulations, surgeons need early feed-back on the effects of temporary vascular occlusion. In surgical practice, commonly the … amplitude of somatosensory evoked potentials (SSEP) is monitored. However, the latency between an ischemic event and the drop of SSEP amplitude may amount to several minutes. Therefore intracranial electroencephalogram (iEEG) is tested for its predictive value.\backslashr\backslashnMETHODS\backslashr\backslashnDuring surgery in 13 patients, SSEP was recorded simultaneously with iEEG. iEEG was analyzed real-time in the frequency domain. Spectral observables of the iEEG were validated on the basis of SSEP by computing the statistical correlation first for the whole data set, then for salient events occurring in the SSEP in the group of patients, and finally for salient events occurring in single patients.\backslashr\backslashnRESULTS\backslashr\backslashnPlacement of subdural strip electrodes was compatible with standard surgical routine. Maximal correlation between time series of iEEG and SSEP was found for relative alpha power, which preceded the drop of SSEP by 7min.\backslashr\backslashnCONCLUSIONS\backslashr\backslashniEEG is feasible during neurosurgical intracranial vascular manipulations. Monitoring relative alpha power detects salient events earlier than SSEP.\backslashr\backslashnSIGNIFICANCE\backslashr\backslashnEarly detection of salient events facilitates early reaction of the surgeon and may thereby aid to further reduce intraoperative morbidity.

Authors: Christian Wess, Johannes Sarnthein, Niklaus Krayenbühl, Markus Scholz, Ekkehard Kunze, Jürgen Meixensberger

Date Published: 1st Dec 2010

Publication Type: Journal article

Genetic regulation of serum phytosterol levels and risk of coronary artery disease
Genetical Statistics and Systems Biology

Abstract (Expand)

BACKGROUND\backslashr\backslashnPhytosterols are plant-derived sterols that are taken up from food and can serve as biomarkers of cholesterol uptake. Serum levels are under tight genetic control. We … used a genomic approach to study the molecular regulation of serum phytosterol levels and potential links to coronary artery disease (CAD).\backslashr\backslashnMETHODS AND RESULTS\backslashr\backslashnA genome-wide association study for serum phytosterols (campesterol, sitosterol, brassicasterol) was conducted in a population-based sample from KORA (Cooperative Research in the Region of Augsburg) (n=1495) with subsequent replication in 2 additional samples (n=1157 and n=1760). Replicated single-nucleotide polymorphisms (SNPs) were tested for association with premature CAD in a metaanalysis of 11 different samples comprising 13 764 CAD cases and 13 630 healthy controls. Genetic variants in the ATP-binding hemitransporter ABCG8 and at the blood group ABO locus were significantly associated with serum phytosterols. Effects in ABCG8 were independently related to SNPs rs4245791 and rs41360247 (combined P=1.6 x 10(-50) and 6.2 x 10(-25), respectively; n=4412). Serum campesterol was elevated 12% for each rs4245791 T-allele. The same allele was associated with 40% decreased hepatic ABCG8 mRNA expression (P=0.009). Effects at the ABO locus were related to SNP rs657152 (combined P=9.4x10(-13)). Alleles of ABCG8 and ABO associated with elevated phytosterol levels displayed significant associations with increased CAD risk (rs4245791 odds ratio, 1.10; 95% CI, 1.06 to 1.14; P=2.2 x 10(-6); rs657152 odds ratio, 1.13; 95% CI, 1.07 to 1.19; P=9.4 x 10(-6)), whereas alleles at ABCG8 associated with reduced phytosterol levels were associated with reduced CAD risk (rs41360247 odds ratio, 0.84; 95% CI, 0.78 to 0.91; P=1.3 x 10(-5)).\backslashr\backslashnCONCLUSION\backslashr\backslashnCommon variants in ABCG8 and ABO are strongly associated with serum phytosterol levels and show concordant and previously unknown associations with CAD.

Authors: Daniel Teupser, Ronny Baber, Uta Ceglarek, Markus Scholz, Thomas Illig, Christian Gieger, Lesca Miriam Holdt, Alexander Leichtle, Karin H. Greiser, Dominik Huster, Patrick Linsel-Nitschke, Arne Schäfer, Peter S. Braund, Laurence Tiret, Klaus Stark, Dorette Raaz-Schrauder, Georg M. Fiedler, Wolfgang Wilfert, Frank Beutner, Stephan Gielen, Anika Grosshennig, Inke R. König, Peter Lichtner, Iris M. Heid, Alexander Kluttig, Nour E El Mokhtari, Diana Rubin, Arif B. Ekici, André Reis, Christoph D. Garlichs, Alistair S. Hall, Gert Matthes, Christian Wittekind, Christian Hengstenberg, Francois Cambien, Stefan Schreiber, Karl Werdan, Thomas Meitinger, Markus Loeffler, Nilesh J. Samani, Jeanette Erdmann, Heinz-Erich Wichmann, Heribert Schunkert, Joachim Thiery

Date Published: 1st Aug 2010

Publication Type: Journal article

Transapical aortic valve implantation in 100 consecutive patients: comparison to propensity-matched conventional aortic valve replacement
Genetical Statistics and Systems Biology

Abstract (Expand)

AIMS\backslashr\backslashnTo evaluate the outcome of transapical aortic valve implantation (TA-AVI) in comparison to conventional surgery.\backslashr\backslashnMETHODS AND RESULTS\backslashr\backslashnOne … hundred consecutive high-risk patients with symptomatic aortic valve stenosis received TA-AVI using the Edwards SAPIEN pericardial xenograft between February 2006 and January 2008. Patient age was 82.7 +/- 5 years, 77 were females, logistic EuroSCORE predicted risk of mortality was 29.4 +/- 13% and Society Thoracic Surgeons score risk for mortality was 15.2 +/- 8.3%. Propensity score analysis was used to identify a control group of patients that underwent conventional aortic valve replacement (C-AVR). Transapical aortic valve implantation was performed successfully in 97 patients, whereas three patients required early conversion. There were no new onset neurological events in the TA-AVI group and early extubation was performed in 82 patients. Echocardiography revealed good valve function with low transvalvular gradients in all patients. Thirty-day survival was 90 +/- 3 vs. 85 +/- 4% for TA-AVI vs. C-AVR, and 1-year survival was 73 +/- 4 vs. 69 +/- 5% (P = 0.55).\backslashr\backslashnCONCLUSION\backslashr\backslashnTransapical aortic valve implantation is a safe, minimally invasive, and off-pump technique to treat high-risk patients with aortic stenosis. Results of the initial 100 patients are good and compare favourably to conventional surgery.

Authors: Thomas Walther, Gerhard Schuler, Michael Andrew Borger, Joerg Kempfert, Jörg Seeburger, Yvonne Rückert, Joerg Ender, Axel Linke, Markus Scholz, Volkmar Falk, Friedrich Wilhelm Mohr

Date Published: 1st Jun 2010

Publication Type: Journal article

A biomathematical model of human thrombopoiesis under chemotherapy.
HaematoOpt - Individualized model-based managing of the next-cycle thrombopenia of CHOEP/CHOP treated patients based on platelets dynamics during the previous cycles

Abstract (Expand)

Intensification of cytotoxic chemotherapy enhances the outcome of several malignancies but is limited by haematotoxicity. While neutropenia and anaemia can be treated with supportive growth factor … applications, thrombocytopenia remains a dose-limiting side effect due to the lack of clinically approved pharmaceutical growth factors. Hence, it is necessary to assess the degree of thrombocytopenia of newly designed intensified regimens in the planning phase of a clinical trial. We present a simple ordinary differential equations model of thrombopoiesis under chemotherapy which maps the dynamics of stem cells, CFU-Mk, megakaryocytes and platelets in spleen and circulation. Major regulatory cytokine of thrombopoiesis is thrombopoietin (TPO) whose production and consumption is explicitly modelled. TPO acts by increasing the number of mitoses of CFU-Mk and increasing the mass and maturation of megakaryocytes. Chemotherapy is modelled by a drug-dose and cell-stage specific acute cell loss. Most of the cell kinetic parameters of the model were taken from literature. Parameters regarding TPO regulation and chemotherapy toxicity were estimated by fitting the predictions of the model to time series data of platelets received from large clinical data sets of patients under seven different chemotherapies. We obtained a good agreement between model and data for all scenarios. Parameter estimates were biologically plausible throughout. For validation, the model also explains data of TPO and platelet dynamics after thrombopheresis taken from literature. We used the model to make clinically relevant predictions. Regarding thrombocytopenia we estimated that the CHOP regimen for the treatment of high-grade non-Hodgkin's lymphoma can be time-intensified to a cycle duration of 12 days while the time-intensified CHOEP regimen would result in severe cumulative toxicity. We conclude that our proposed model proved validity for both, different chemotherapeutic regimens and thrombopheresis as well. It is useful to assess the thrombocytopenic risk in the planning phase of a clinical trial.

Authors: M. Scholz, A. Gross, M. Loeffler

Date Published: 21st May 2010

Publication Type: Not specified

ANRIL expression is associated with atherosclerosis risk at chromosome 9p21
Genetical Statistics and Systems Biology

Abstract (Expand)

OBJECTIVE\backslashr\backslashnWe tested the hypothesis that expression of transcripts adjacent to the chromosome 9p21 (Chr9p21) locus of coronary artery disease was affected by the genotype at this … locus and associated with atherosclerosis risk.\backslashr\backslashnMETHODS AND RESULTS\backslashr\backslashnWe replicated the locus for coronary artery disease (P=0.007; OR=1.28) and other manifestations of atherosclerosis such as carotid plaque (P=0.003; OR=1.31) in the Leipzig Heart Study, a cohort of 1134 patients with varying degree of angiographically assessed coronary artery disease. Expression analysis in peripheral blood mononuclear cells (n=1098) revealed that transcripts EU741058 and NR_003529 of antisense noncoding RNA in the INK4 locus (ANRIL) were significantly increased in carriers of the risk haplotype (P=2.1x10(-12) and P=1.6x10(-5), respectively). In contrast, transcript DQ485454 remained unaffected, suggesting differential expression of ANRIL transcripts at Chr9p21. Results were replicated in whole blood (n=769) and atherosclerotic plaque tissue (n=41). Moreover, expression of ANRIL transcripts was directly correlated with severity of atherosclerosis (EU741058 and NR_003529; P=0.02 and P=0.001, respectively). No consistent association of Chr9p21 or atherosclerosis was found with expression of other genes such as CDKN2A, CDKN2B, C9orf53, and MTAP.\backslashr\backslashnCONCLUSIONS\backslashr\backslashnOur data provide robust evidence for an association of ANRIL but not CDKN2A, CDKN2B, C9orf53, and MTAP, with atherosclerosis and Chr9p21 genotype in a large cohort.

Authors: Lesca Miriam Holdt, Frank Beutner, Markus Scholz, Stephan Gielen, Gábor Gäbel, Hendrik Bergert, Gerhard Schuler, Joachim Thiery, Daniel Teupser

Date Published: 1st Mar 2010

Publication Type: Journal article

Transplantation of placenta-derived mesenchymal stromal cells upon experimental stroke in rats
Genetical Statistics and Systems Biology

Abstract (Expand)

The beneficial effects of bone marrow-derived mesenchymal stromal cell (MSC) administration following experimental stroke have already been described. Despite several promising characteristics, … placenta-derived MSC have not been used in models of focal ischemia. The aim of the current study is to investigate the impact of intravenously transplanted placenta-derived MSC on post-stroke recovery. Permanent occlusion of the middle cerebral artery was induced in spontaneously hypertensive rats. MSC were obtained from the human maternal or fetal placenta and intravenously administered after 24 h (single transplantation) or after 8 h and 24 h (dual transplantation). Sensorimotor deficits were quantified for 60 days using the beam walk test and the modified Neurological Severity Score system. Infarct volume was determined in vivo by means of magnetic resonance imaging on days 1, 8, 29 and 60. Astroglial reactivity was semiquantitatively ascertained within a small and a broad region adjacent to the lesion border. The double infusion of placental MSC was superior to single transplantation in the functional tests. However, a significant difference to the control group in all outcome parameters was observed only for maternally derived MSC. These findings suggest that placental tissue constitutes a promising source for experimental stroke therapies. The beneficial effects of bone marrow-derived mesenchymal stromal cell (MSC) administration following experimental stroke have already been described. Despite several promising characteristics, placenta-derived MSC have not been used in models of focal ischemia. The aim of the current study is to investigate the impact of intravenously transplanted placenta-derived MSC on post-stroke recovery. Permanent occlusion of the middle cerebral artery was induced in spontaneously hypertensive rats. MSC were obtained from the human maternal or fetal placenta and intravenously administered after 24 h (single transplantation) or after 8 h and 24 h (dual transplantation). Sensorimotor deficits were quantified for 60 days using the beam walk test and the modified Neurological Severity Score system. Infarct volume was determined in vivo by means of magnetic resonance imaging on days 1, 8, 29 and 60. Astroglial reactivity was semiquantitatively ascertained within a small and a broad region adjacent to the lesion border. The double infusion of placental MSC was superior to single transplantation in the functional tests. However, a significant difference to the control group in all outcome parameters was observed only for maternally derived MSC. These findings suggest that placental tissue constitutes a promising source for experimental stroke therapies.

Authors: Alexander Kranz, Daniel-Christoph Wagner, Manja Kamprad, Markus Scholz, Uwe Richard Schmidt, Franziska Nitzsche, Zami Aberman, Frank Emmrich, Ute-Maria Riegelsberger, Johannes Boltze

Date Published: 1st Feb 2010

Publication Type: Journal article

Comparison of estimators for measures of linkage disequilibrium
Genetical Statistics and Systems Biology

Abstract (Expand)

The measurement of biallelic pair-wise association called linkage disequilibrium (LD) is an important issue in order to understand the genomic architecture. A plethora of measures of association in two … by two tables have been proposed in the literature. Beside the problem of choosing an appropriate measure, the problem of their estimation has been neglected in the literature. It needs to be emphasized that the definition of a measure and the choice of an estimator function for it are conceptually unrelated tasks. In this paper, we compare the performance of various estimators for the three popular LD measures D’, r and Y in a simulation study for small to moderate samples sizes (N\textless=500). The usual frequency-plug-in estimators can lead to unreliable or undefined estimates. Estimators based on the computationally expensive volume measures have been proposed recently as a remedy to this well-known problem. We confirm that volume estimators have better expected mean square error than the naive plug-in estimators. But they are outperformed by estimators plugging-in easy to calculate non-informative Bayesian probability estimates into the theoretical formulae for the measures. Fully Bayesian estimators with non-informative Dirichlet priors have comparable accuracy but are computationally more expensive. We recommend the use of non-informative Bayesian plug-in estimators based on Jeffreys’ prior, in particular when dealing with SNP array data where the occurrence of small table entries and table margins is likely.

Authors: Markus Scholz, Dirk Hasenclever

Date Published: 2010

Publication Type: Journal article

A pharmacokinetic model of filgrastim and pegfilgrastim application in normal mice and those with cyclophosphamide-induced granulocytopaenia
Genetical Statistics and Systems Biology

Abstract (Expand)

OBJECTIVES\backslashr\backslashnRecombinant human granulocyte colony-stimulating factor (rhG-CSF) is widely used as treatment for granulocytopaenia during cytotoxic chemotherapy; however, optimal … scheduling of this pharmaceutical is unknown. Biomathematical models can help to pre-select optimal application schedules but precise pharmacokinetic properties of the pharmaceuticals are required at first. In this study, we have aimed to construct a pharmacokinetic model of G-CSF derivatives filgrastim and pegfilgrastim in mice.\backslashr\backslashnMETHODS\backslashr\backslashnHealthy CD-1 mice and those with cyclophosphamide-induced granulocytopaenia were studied after administration of filgrastim and pegfilgrastim in different dosing and timing schedules. Close meshed time series of granulocytes and G-CSF plasma concentrations were determined. An ordinary differential equations model of pharmacokinetics was constructed on the basis of known mechanisms of drug distribution and degradation.\backslashr\backslashnRESULTS\backslashr\backslashnPredictions of the model fit well with all experimental data for both filgrastim and pegfilgrastim. We obtained a unique parameter setting for all experimental scenarios. Differences in pharmacokinetics between filgrastim and pegfilgrastim can be explained by different estimates of model parameters rather than by different model mechanisms. Parameter estimates with respect to distribution and clearance of the drug derivatives are in agreement with qualitative experimental results.\backslashr\backslashnCONCLUSION\backslashr\backslashnDynamics of filgrastim and pegfilgrastim plasma levels can be explained by the same pharmacokinetic model but different model parameters. Beause of a strong clearance mechanism mediated by granulocytes, granulocytotic and granulocytopaenic conditions must be studied simultaneously to construct a reliable model. The pharmacokinetic model will be extended to a murine model of granulopoiesis under chemotherapy and G-CSF application.

Authors: Markus Scholz, Manuela Ackermann, Christoph Engel, Frank Emmrich, Markus Loeffler, Manja Kamprad

Date Published: 1st Dec 2009

Publication Type: Journal article

Pharmacokinetic and pharmacodynamic modelling of the novel human granulocyte colony-stimulating factor derivative Maxy-G34 and pegfilgrastim in rats
Genetical Statistics and Systems Biology

Abstract (Expand)

OBJECTIVES\backslashr\backslashnThis study aims to compare pharmacokinetics and pharmacodynamics of pegfilgrastim, a pharmaceutical recombinant human granulocyte colony-stimulating factor (rhG-CSF), … with that of a newly developed reagent, Maxy-G34. This comparison was performed using rat experiments and biomathematical modelling of granulopoiesis.\backslashr\backslashnMETHODS\backslashr\backslashnHealthy rats and those with cyclophosphamide-induced neutropenia were treated with either pegfilgrastim or Maxy-G34 under various schedules. Time courses of absolute neutrophil count (ANC) and G-CSF serum level were measured and we constructed a combined pharmacokinetic/pharmacodynamic model of both drugs. Neutropenic episodes were assessed by experimental data and model simulations.\backslashr\backslashnRESULTS\backslashr\backslashnBoth Pegfilgrastim and Maxy-G34 showed strong dose-dependent efficacy in reducing neutropenic episodes. However, time courses of ANC and G-CSF serum levels were markedly different. The biomathematical model showed good agreement with these data. We estimated that differences between the two drugs could be explained by lower bioavailability and reduced elimination of Maxy-G34. Based on the data and model interpolations, we estimated that Maxy-G34 is superior in reducing neutropenic episodes. Also, we predicted that G-CSF administration 48 h after cyclophosphamide would be superior to its administration after 2 or 24 h, for both derivatives.\backslashr\backslashnCONCLUSION\backslashr\backslashnMaxy-G34 is a highly potent drug for stimulation of neutrophil production in rats. By our modelling approach, we quantified differences between Maxy-G34 and pegfilgrastim, related to pharmacokinetic parameters. Model simulations can be used to estimate optimal dosing and timing options in the present preclinical rat model.

Authors: Markus Scholz, Christoph Engel, D. Apt, S. L. Sankar, E. Goldstein, Markus Loeffler

Date Published: 1st Dec 2009

Publication Type: Journal article

Genetic variation and recent positive selection in worldwide human populations: evidence from nearly 1 million SNPs
Genetical Statistics and Systems Biology

Abstract (Expand)

BACKGROUND\backslashr\backslashnGenome-wide scans of hundreds of thousands of single-nucleotide polymorphisms (SNPs) have resulted in the identification of new susceptibility variants to common diseases … and are providing new insights into the genetic structure and relationships of human populations. Moreover, genome-wide data can be used to search for signals of recent positive selection, thereby providing new insights into the genetic adaptations that occurred as modern humans spread out of Africa and around the world.\backslashr\backslashnMETHODOLOGY\backslashr\backslashnWe genotyped approximately 500,000 SNPs in 255 individuals (5 individuals from each of 51 worldwide populations) from the Human Genome Diversity Panel (HGDP-CEPH). When merged with non-overlapping SNPs typed previously in 250 of these same individuals, the resulting data consist of over 950,000 SNPs. We then analyzed the genetic relationships and ancestry of individuals without assigning them to populations, and we also identified candidate regions of recent positive selection at both the population and regional (continental) level.\backslashr\backslashnCONCLUSIONS\backslashr\backslashnOur analyses both confirm and extend previous studies; in particular, we highlight the impact of various dispersals, and the role of substructure in Africa, on human genetic diversity. We also identified several novel candidate regions for recent positive selection, and a gene ontology (GO) analysis identified several GO groups that were significantly enriched for such candidate genes, including immunity and defense related genes, sensory perception genes, membrane proteins, signal receptors, lipid binding/metabolism genes, and genes involved in the nervous system. Among the novel candidate genes identified are two genes involved in the thyroid hormone pathway that show signals of selection in African Pygmies that may be related to their short stature.

Authors: David López Herráez, Marc Bauchet, Kun Tang, Christoph Theunert, Irina Pugach, Jing Li, Madhusudan R. Nandineni, Arnd Gross, Markus Scholz, Mark Stoneking

Date Published: 18th Nov 2009

Publication Type: Journal article

Association of the X-chromosomal genes TIMP1 and IL9R with rheumatoid arthritis
Genetical Statistics and Systems Biology

Abstract (Expand)

OBJECTIVE\backslashr\backslashnRheumatoid arthritis (RA) is an inflammatory joint disease with features of an autoimmune disease with female predominance. Candidate genes located on the X-chromosome … were selected for a family trio-based association study.\backslashr\backslashnMETHODS\backslashr\backslashnA total of 1452 individuals belonging to 3 different sample sets were genotyped for 16 single-nucleotide polymorphisms (SNP) in 7 genes. The first 2 sets consisted of 100 family trios, each of French Caucasian origin, and the third of 284 additional family trios of European Caucasian origin. Subgroups were analyzed according to sex of patient and presence of anti-cyclic citrullinated peptide (anti-CCP) autoantibodies.\backslashr\backslashnRESULTS\backslashr\backslashnFour SNP were associated with RA in the first sample set and were genotyped in the second set. In combined analysis of sets 1 and 2, evidence remained for association of 3 SNP in the genes UBA1, TIMP1, and IL9R. These were again genotyped in the third sample set. Two SNP were associated with RA in the joint analysis of all samples: rs6520278 (TIMP1) was associated with RA in general (p = 0.035) and rs3093457 (IL9R) with anti-CCP-positive RA patients (p = 0.037) and male RA patients (p = 0.010). A comparison of the results with data from whole-genome association studies further supports an association of RA with TIMPL The sex-specific association of rs3093457 (IL9R) was supported by the observation that men homozygous for rs3093457-CC are at a significantly higher risk to develop RA than women (risk ratio male/female = 2.98; p = 0.048).\backslashr\backslashnCONCLUSION\backslashr\backslashnWe provide evidence for an association of at least 2 X-chromosomal genes with RA: TIMP1 (rs6520278) and IL9R (rs3093457).

Authors: Jana Burkhardt, Elisabeth Petit-Teixeira, Vitor Hugo Teixeira, Holger Kirsten, Sophie Garnier, Sandra Ruehle, Christian Oeser, Grit Wolfram, Markus Scholz, Paola Migliorini, Alejandro Balsa, Renè Westhovens, Pilar Barrera, Helena Alves, Dora Pascual-Salcedo, Stefano Bombardieri, Jan Dequeker, Timothy R. Radstake, Piet van Riel, Leo van de Putte, Thomas Bardin, Bernard Prum, Ulrike Buchegger-Podbielski, Frank Emmrich, Inga Melchers, François Cornelis, Peter Ahnert

Date Published: 8th Oct 2009

Publication Type: Journal article

Anesthesia management for transapical transcatheter aortic valve implantation: a case series
Genetical Statistics and Systems Biology

Abstract (Expand)

OBJECTIVE\backslashr\backslashnThe purpose of this study was to review the management of anesthesia for transapical transcatheter aortic valve implantation.\backslashr\backslashnDESIGN\backslashr\backslashnRetrospective … review of collected data.\backslashr\backslashnSETTING\backslashr\backslashnUniversity-affiliated heart center.\backslashr\backslashnPARTICIPANTS\backslashr\backslashnOne hundred consecutive patients with severe aortic stenosis.\backslashr\backslashnINTERVENTIONS\backslashr\backslashnGeneral anesthesia followed by an established fast-track protocol.\backslashr\backslashnMATERIALS AND METHODS\backslashr\backslashnA total of 100 patients with significant AS received transapical transcatheter aortic valve implantation. The patients were treated following a fast-track protocol. The mean arterial pressure was maintained above 65 mmHg by volume and/or inotropes during the procedure. The mean arterial pressure was increased above 75 mmHg to avoid hemodynamic deterioration before starting rapid ventricular pacing for the balloon valvuloplasty and the valve implantation. Transesophageal echocardiography was used to assess valve size and for hemodynamic monitoring. Eighty-one patients were treated completely off pump. There was a significant decline in mean arterial pressure from pre- to postvalvuloplasty (74.7 +/- 9.1 mmHg v 63.6 +/- 11.3 mmHg, p \textless 0.001) and from pre- to postimplantation (76.5 +/- 12.6 mmHg v 67.2 +/- 12.7, p \textless 0.001). The first 10 patients in the study intentionally were placed on cardiopulmonary bypass, and 9 patients required cardiopulmonary bypass because of hemodynamic deterioration.\backslashr\backslashnCONCLUSION\backslashr\backslashnA well-designed anesthetic plan as well as an understanding of the surgical procedure and the hemodynamic effects of rapid ventricular pacing are required to ensure successful outcomes in this new surgical option for high-risk patients.

Authors: Jens Fassl, Thomas Walther, Heinrich Volker Groesdonk, Joerg Kempfert, Michael Andrew Borger, Markus Scholz, Chirojit Mukherjee, Axel Linke, Gerhard Schuler, Friedrich Wilhelm Mohr, Joerg Ender

Date Published: 1st Jun 2009

Publication Type: Journal article

Antiphospholipidsyndrom und retinale venöse Verschlüsse. Metaanalyse publizierter Studien
Genetical Statistics and Systems Biology

Abstract (Expand)

The role of antiphospholipid syndrome (APS) in the pathogenesis of retinal vein occlusion has been discussed for several years. Conflicting results of the published studies are caused by small numbers … of investigated patients and lack of control groups. We performed a meta-analysis of all case-control studies published up to July 2007 that investigated the prevalence of APS according to current diagnostic criteria for this syndrome.The results of meta-analysis show a significantly higher prevalence of APS in patients with retinal vein occlusion compared with controls. Patients with APS are treated with anticoagulants to reduce the risk of recurrence of thrombosis. Therefore, screening for APS seems to be indicated in all patients with retinal vein occlusion, and, in the case of a positive result, initiation of anticoagulation. For patients with retinal vein occlusion with APS, no data are currently available regarding the recurrence of thrombosis. To give a clear recommendation, a prospective randomized study is required to investigate the benefit of anticoagulation.

Authors: Matus Rehak, M. Müller, Markus Scholz, J. Wiercinska, D. Niederwieser, Peter Wiedemann

Date Published: 1st May 2009

Publication Type: Journal article

Leipziger \textquotedblFast-track\textquotedbl-Protokoll in der Kardioanästhesie. Effektiv, sicher und ökonomisch sinnvoll
Genetical Statistics and Systems Biology

Abstract (Expand)

BACKGROUND\backslashr\backslashnIn November 2005 a complex, multimodal anesthesia fast-track protocol (FTP) was introduced for elective cardiac surgery patients in the Cardiac Center of the University … of Leipzig which included changing from an opioid regime to remifentanil and postoperative treatment in a special post-anesthesia recovery and care unit. The goal was to speed up recovery times while maintaining safety and improving costs.\backslashr\backslashnMETHOD\backslashr\backslashnA total of 421 patients who underwent the FTP and were treated in the special recovery room were analyzed retrospectively. These patients were compared with patients who had been treated by a standard protocol (SP) prior to instituting the FTP. Primary outcomes were time to extubation, length of stay in the intensive care unit (ICU) and treatment costs.\backslashr\backslashnRESULTS\backslashr\backslashnThe times to extubation were significantly shorter in the FTP group with 75 min (range 45-110 min) compared to 900 min (range 600-1140 min) in the SP group. Intensive care unit stay and hospital length of stay were also significantly shorter in the FTP group (p\textless0.01). The reduction of treatment costs of intensive care for FTP patients was 53.5% corresponding to savings of EUR 738 per patient in the FTP group compared with the SP group.\backslashr\backslashnCONCLUSIONS\backslashr\backslashnThe Leipzig fast-track protocol for cardio-anesthesia including the central elements of switching opiate therapy to remifentanil and switching patient recovery to a special post-anesthesia recovery and care unit, shortened therapy times, is safe and economically effective. BACKGROUND In November 2005 a complex, multimodal anesthesia fast-track protocol (FTP) was introduced for elective cardiac surgery patients in the Cardiac Center of the University of Leipzig which included changing from an opioid regime to remifentanil and postoperative treatment in a special post-anesthesia recovery and care unit. The goal was to speed up recovery times while maintaining safety and improving costs. METHOD A total of 421 patients who underwent the FTP and were treated in the special recovery room were analyzed retrospectively. These patients were compared with patients who had been treated by a standard protocol (SP) prior to instituting the FTP. Primary outcomes were time to extubation, length of stay in the intensive care unit (ICU) and treatment costs. RESULTS The times to extubation were significantly shorter in the FTP group with 75 min (range 45-110 min) compared to 900 min (range 600-1140 min) in the SP group. Intensive care unit stay and hospital length of stay were also significantly shorter in the FTP group (p\textless0.01). The reduction of treatment costs of intensive care for FTP patients was 53.5% corresponding to savings of EUR 738 per patient in the FTP group compared with the SP group. CONCLUSIONS The Leipzig fast-track protocol for cardio-anesthesia including the central elements of switching opiate therapy to remifentanil and switching patient recovery to a special post-anesthesia recovery and care unit, shortened therapy times, is safe and economically effective.

Authors: D. Häntschel, Jens Fassl, Markus Scholz, Marcus Sommer, Anne-Kathrin Funkat, M. Wittmann, Joerg Ender

Date Published: 1st Apr 2009

Publication Type: Journal article

Association of MICA with rheumatoid arthritis independent of known HLA-DRB1 risk alleles in a family-based and a case control study
Genetical Statistics and Systems Biology

Abstract (Expand)

INTRODUCTION\backslashr\backslashnThe gene MICA encodes the protein major histocompatibility complex class I polypeptide-related sequence A. It is expressed in synovium of patients with rheumatoid … arthritis (RA) and its implication in autoimmunity is discussed. We analyzed the association of genetic variants of MICA with susceptibility to RA.\backslashr\backslashnMETHODS\backslashr\backslashnInitially, 300 French Caucasian individuals belonging to 100 RA trio families were studied. An additional 100 independent RA trio families and a German Caucasian case-control cohort (90/182 individuals) were available for replication. As MICA is situated in proximity to known risk alleles of the HLA-DRB1 locus, our analysis accounted for linkage disequilibrium either by analyzing the subgroup consisting of parents not carrying HLA-DRB1 risk alleles with transmission disequilibrium test (TDT) or by implementing a regression model including all available data. Analysis included a microsatellite polymorphism (GCT)n and single-nucleotide polymorphisms (SNPs) rs3763288 and rs1051794.\backslashr\backslashnRESULTS\backslashr\backslashnIn contrast to the other investigated polymorphisms, the non-synonymously coding SNP MICA-250 (rs1051794, Lys196Glu) was strongly associated in the first family cohort (TDT: P = 0.014; regression model: odds ratio [OR] 0.46, 95% confidence interval [CI] 0.25 to 0.82, P = 0.007). Although the replication family sample showed only a trend, combined family data remained consistent with the hypothesis of MICA-250 association independent from shared epitope (SE) alleles (TDT: P = 0.027; regression model: OR 0.56, 95% CI 0.38 to 0.83, P = 0.003). We also replicated the protective association of MICA-250A within a German Caucasian cohort (OR 0.31, 95% CI 0.1 to 0.7, P = 0.005; regression model: OR 0.6, 95% CI 0.37 to 0.96, P = 0.032). We showed complete linkage disequilibrium of MICA-250 (D’ = 1, r2= 1) with the functional MICA variant rs1051792 (D’ = 1, r2= 1). As rs1051792 confers differential allelic affinity of MICA to the receptor NKG2D, this provides a possible functional explanation for the observed association.\backslashr\backslashnCONCLUSIONS\backslashr\backslashnWe present evidence for linkage and association of MICA-250 (rs1051794) with RA independent of known HLA-DRB1 risk alleles, suggesting MICA as an RA susceptibility gene. However, more studies within other populations are necessary to prove the general relevance of this polymorphism for RA.

Authors: Holger Kirsten, Elisabeth Petit-Teixeira, Markus Scholz, Dirk Hasenclever, Helene Hantmann, Dirk Heider, Ulf Wagner, Ulrich Sack, Vitor Hugo Teixeira, Bernard Prum, Jana Burkhardt, Céline Pierlot, Frank Emmrich, François Cornelis, Peter Ahnert

Date Published: 2009

Publication Type: Journal article

Effectiveness of cytopenia prophylaxis for different filgrastim and pegfilgrastim schedules in a chemotherapy mouse model
Genetical Statistics and Systems Biology

Abstract (Expand)

OBJECTIVES Recombinant human granulocyte colony-stimulating factor (rhG-CSF) is widely used to treat neutropenia during cytotoxic chemotherapy. The optimal scheduling of rhG-CSF is unknown and can …n hardly be tested in clinical studies due to numerous therapy parameters affecting outcome (chemotherapeutic regimen, rhG-CSF schedules, individual covariables). Motivated by biomathematical model simulations, we aim to investigate different rhG-CSF schedules in a preclinical chemotherapy mouse model. METHODS The time course of hematotoxicity was studied in CD-1 mice after cyclophosphamide (CP) administration. Filgrastim was applied concomitantly in a 2 x 3-factorial design of two dosing options (2 x 20 mug and 4 x 10 mug) and three timing options (directly, one, and two days after CP). Alternatively, a single dose of 40 mug pegfilgrastim was applied at the three timing options. The resulting cytopenia was compared among the schedules. RESULTS Dosing and timing had a significant influence on the effectiveness of filgrastim schedules whereas for pegfilgrastim the timing effect was irrelevant. The best filgrastim and pegfilgrastim schedules exhibited equivalent toxicity. Monocytes dynamics performed analogously to granulocytes. All schedules showed roughly the same lymphotoxicity. CONCLUSION We conclude that effectiveness of filgrastim application depends heavily on its scheduling during chemotherapy. There is an optimum of timing. Dose splitting is better than concentrated applications. Effectiveness of pegfilgrastim is less dependent on timing. OBJECTIVES Recombinant human granulocyte colony-stimulating factor (rhG-CSF) is widely used to treat neutropenia during cytotoxic chemotherapy. The optimal scheduling of rhG-CSF is unknown and can hardly be tested in clinical studies due to numerous therapy parameters affecting outcome (chemotherapeutic regimen, rhG-CSF schedules, individual covariables). Motivated by biomathematical model simulations, we aim to investigate different rhG-CSF schedules in a preclinical chemotherapy mouse model. METHODS The time course of hematotoxicity was studied in CD-1 mice after cyclophosphamide (CP) administration. Filgrastim was applied concomitantly in a 2 x 3-factorial design of two dosing options (2 x 20 mug and 4 x 10 mug) and three timing options (directly, one, and two days after CP). Alternatively, a single dose of 40 mug pegfilgrastim was applied at the three timing options. The resulting cytopenia was compared among the schedules. RESULTS Dosing and timing had a significant influence on the effectiveness of filgrastim schedules whereas for pegfilgrastim the timing effect was irrelevant. The best filgrastim and pegfilgrastim schedules exhibited equivalent toxicity. Monocytes dynamics performed analogously to granulocytes. All schedules showed roughly the same lymphotoxicity. CONCLUSION We conclude that effectiveness of filgrastim application depends heavily on its scheduling during chemotherapy. There is an optimum of timing. Dose splitting is better than concentrated applications. Effectiveness of pegfilgrastim is less dependent on timing.

Authors: Markus Scholz, Manuela Ackermann, Frank Emmrich, Markus Loeffler, Manja Kamprad

Date Published: 2009

Publication Type: Journal article

Neuronal hypoxia in vitro: investigation of therapeutic principles of HUCB-MNC and CD133+ stem cells
Genetical Statistics and Systems Biology

Abstract (Expand)

BACKGROUND\backslashr\backslashnThe therapeutic capacity of human umbilical cord blood mononuclear cells (HUCB-MNC) and stem cells derived thereof is documented in animal models of focal cerebral … ischemia, while mechanisms behind the reduction of lesion size and the observed improvement of behavioral skills still remain poorly understood.\backslashr\backslashnMETHODS\backslashr\backslashnA human in vitro model of neuronal hypoxia was used to address the impact of total HUCB-MNC (tMNC), a stem cell enriched fraction (CD133+, 97.38% CD133-positive cells) and a stem cell depleted fraction (CD133-, 0.06% CD133-positive cells) of HUCB-MNC by either direct or indirect co-cultivation with post-hypoxic neuronal cells (differentiated SH-SY5Y). Over three days, development of apoptosis and necrosis of neuronal cells, chemotaxis of MNC and production of chemokines (CCL2, CCL3, CCL5, CXCL8, CXCL9) and growth factors (G-CSF, GM-CSF, VEGF, bFGF) were analyzed using fluorescence microscopy, FACS and cytometric bead array.\backslashr\backslashnRESULTS\backslashr\backslashntMNC, CD133+ and surprisingly CD133- reduced neuronal apoptosis in direct co-cultivations significantly to levels in the range of normoxic controls (7% +/- 3%). Untreated post-hypoxic control cultures showed apoptosis rates of 85% +/- 11%. tMNC actively migrated towards injured neuronal cells. Both co-cultivation types using tMNC or CD133- reduced apoptosis comparably. CD133- produced high concentrations of CCL3 and neuroprotective G-CSF within indirect co-cultures. Soluble factors produced by CD133+ cells were not detectable in direct co-cultures.\backslashr\backslashnCONCLUSION\backslashr\backslashnOur data show that heterogeneous tMNC and even CD133-depleted fractions have the capability not only to reduce apoptosis in neuronal cells but also to trigger the retaining of neuronal phenotypes. BACKGROUND The therapeutic capacity of human umbilical cord blood mononuclear cells (HUCB-MNC) and stem cells derived thereof is documented in animal models of focal cerebral ischemia, while mechanisms behind the reduction of lesion size and the observed improvement of behavioral skills still remain poorly understood. METHODS A human in vitro model of neuronal hypoxia was used to address the impact of total HUCB-MNC (tMNC), a stem cell enriched fraction (CD133+, 97.38% CD133-positive cells) and a stem cell depleted fraction (CD133-, 0.06% CD133-positive cells) of HUCB-MNC by either direct or indirect co-cultivation with post-hypoxic neuronal cells (differentiated SH-SY5Y). Over three days, development of apoptosis and necrosis of neuronal cells, chemotaxis of MNC and production of chemokines (CCL2, CCL3, CCL5, CXCL8, CXCL9) and growth factors (G-CSF, GM-CSF, VEGF, bFGF) were analyzed using fluorescence microscopy, FACS and cytometric bead array. RESULTS tMNC, CD133+ and surprisingly CD133- reduced neuronal apoptosis in direct co-cultivations significantly to levels in the range of normoxic controls (7% +/- 3%). Untreated post-hypoxic control cultures showed apoptosis rates of 85% +/- 11%. tMNC actively migrated towards injured neuronal cells. Both co-cultivation types using tMNC or CD133- reduced apoptosis comparably. CD133- produced high concentrations of CCL3 and neuroprotective G-CSF within indirect co-cultures. Soluble factors produced by CD133+ cells were not detectable in direct co-cultures. CONCLUSION Our data show that heterogeneous tMNC and even CD133-depleted fractions have the capability not only to reduce apoptosis in neuronal cells but also to trigger the retaining of neuronal phenotypes.

Authors: Doreen M. Reich, Susann Hau, Tobias Stahl, Markus Scholz, Wilfried Naumann, Frank Emmrich, Johannes Boltze, Manja Kamprad

Date Published: 1st Dec 2008

Publication Type: Journal article

The prevalence of activated protein C (APC) resistance and factor V Leiden is significantly higher in patients with retinal vein occlusion without general risk factors. Case-control study and meta-analysis.
Genetical Statistics and Systems Biology

Abstract (Expand)

Several small case-control studies have investigated whether factor V Leiden (FVL) is a risk factor for retinal vein occlusion (RVO) and generated conflicting data. To clarify this question we performed … a large two-centre case-control study and a meta-analysis of published studies. Two hundred seven consecutive patients with RVO and a control group of 150 subjects were screened between 1996 and 2006. A systematic meta-analysis was done combining our study with further 17 published European case-control studies. APC resistance was detected in 16 out of 207 (7.7%) patients and eight out of 150 (5.3%) controls. The odds ratio (OR) estimated was 1.49 with a (non-significant) 95% confidence interval (CI) of 0.62-3.57. The meta-analysis including 18 studies with a total of 1,748 patients and 2,716 controls showed a significantly higher prevalence of FVL in patients with RVO compared to healthy controls (combined OR 1.66; 95% CI 1.19-2.32). All single studies combined in the meta-analysis were too small to reliably detect the effect individually. This explains the seemingly contradictory data in the literature. In conclusion, the prevalence of APC resistance (and FVL) is increased in patients with RVO compared to controls, but the effect is only moderate. Therefore, there is no indication for general screening of factor V mutation in all patients with RVO. We recommend this test to be performed in patients older than 50 years with an additional history of thromboembolic event and in younger patients without general risk factors like hypertension.

Authors: Matus Rehak, Jiri Rehak, Marc Müller, Susanne Faude, Frank Faude, Annelie Siegemund, Vera Krcova, Ludek Slavik, Dirk Hasenclever, Markus Scholz, Peter Wiedemann

Date Published: 9th Apr 2008

Publication Type: Journal article

Cardiac surgery fast-track treatment in a postanesthetic care unit: six-month results of the Leipzig fast-track concept
Genetical Statistics and Systems Biology

Abstract (Expand)

BACKGROUND\backslashr\backslashnThe authors compared the safety and efficacy of a newly developed fast-track concept at their center, including implementation of a direct admission postanesthetic care … unit, to standard perioperative management.\backslashr\backslashnMETHODS\backslashr\backslashnAll fast-track patients treated within the first 6 months of implementation of our direct admission postanesthetic care unit were matched via propensity scores and compared with a historical control group of patients who underwent cardiac surgery prior to fast-track implementation.\backslashr\backslashnRESULTS\backslashr\backslashnA total of 421 fast-track patients were matched successfully to 421 control patients. The two groups of patients had a similar age (64 +/- 13 vs. 64 +/- 12 yr for fast-track vs. control, P = 0.45) and European System for Cardiac Operative Risk Evaluation-predicted risk of mortality (4.8 +/- 6.1% vs. 4.6 +/- 5.1%, P = 0.97). Fast-track patients had significantly shorter times to extubation (75 min [45-110] vs. 900 min [600-1140]), as well as shorter lengths of stay in the postanesthetic or intensive care unit (4 h [3.0-5] vs. 20 h [16-25]), intermediate care unit (21 h [17-39] vs. 26 h [19-49]), and hospital (10 days [8-12] vs. 11 days [9-14]) (expressed as median and interquartile range, all P \textless 0.01). Fast-track patients also had a lower risk of postoperative low cardiac output syndrome (0.5% vs. 2.9%, P \textless 0.05) and mortality (0.5% vs. 3.3%, P \textless 0.01).\backslashr\backslashnCONCLUSION\backslashr\backslashnThe Leipzig fast-track protocol is a safe and effective method to manage cardiac surgery patients after a variety of operations. BACKGROUND The authors compared the safety and efficacy of a newly developed fast-track concept at their center, including implementation of a direct admission postanesthetic care unit, to standard perioperative management. METHODS All fast-track patients treated within the first 6 months of implementation of our direct admission postanesthetic care unit were matched via propensity scores and compared with a historical control group of patients who underwent cardiac surgery prior to fast-track implementation. RESULTS A total of 421 fast-track patients were matched successfully to 421 control patients. The two groups of patients had a similar age (64 +/- 13 vs. 64 +/- 12 yr for fast-track vs. control, P = 0.45) and European System for Cardiac Operative Risk Evaluation-predicted risk of mortality (4.8 +/- 6.1% vs. 4.6 +/- 5.1%, P = 0.97). Fast-track patients had significantly shorter times to extubation (75 min [45-110] vs. 900 min [600-1140]), as well as shorter lengths of stay in the postanesthetic or intensive care unit (4 h [3.0-5] vs. 20 h [16-25]), intermediate care unit (21 h [17-39] vs. 26 h [19-49]), and hospital (10 days [8-12] vs. 11 days [9-14]) (expressed as median and interquartile range, all P \textless 0.01). Fast-track patients also had a lower risk of postoperative low cardiac output syndrome (0.5% vs. 2.9%, P \textless 0.05) and mortality (0.5% vs. 3.3%, P \textless 0.01). CONCLUSION The Leipzig fast-track protocol is a safe and effective method to manage cardiac surgery patients after a variety of operations.

Authors: Joerg Ender, Michael Andrew Borger, Markus Scholz, Anne-Kathrin Funkat, Nadeem Anwar, Marcus Sommer, Friedrich Wilhelm Mohr, Jens Fassl

Date Published: 2008

Publication Type: Journal article

Evidence for neuroprotective properties of human umbilical cord blood cells after neuronal hypoxia in vitro
Genetical Statistics and Systems Biology

Abstract (Expand)

BACKGROUND\backslashr\backslashnOne of the most promising options for treatment of stroke using adult stem cells are human umbilical cord blood (HUCB) cells that were already approved for therapeutic … efficacy in vivo. However, complexity of animal models has thus far limited the understanding of beneficial cellular mechanisms. To address the influence of HUCB cells on neuronal tissue after stroke we established and employed a human in vitro model of neuronal hypoxia using fully differentiated vulnerable SH-SY5Y cells. These cells were incubated under an oxygen-reduced atmosphere (O2\textless 1%) for 48 hours. Subsequently, HUCB mononuclear cells (MNC) were added to post-hypoxic neuronal cultures. These cultures were characterized regarding to the development of apoptosis and necrosis over three days. Based on this we investigated the therapeutic influence of HUCB MNC on the progression of apoptotic cell death. The impact of HUCB cells and hypoxia on secretion of neuroprotective and inflammatory cytokines, chemokines and expression of adhesion molecules was proved.\backslashr\backslashnRESULTS\backslashr\backslashnHypoxic cultivation of neurons initially induced a rate of 26% +/- 13% of apoptosis. Hypoxia also caused an enhanced expression of Caspase-3 and cleaved poly(ADP-ribose) polymerase (PARP). Necrosis was only detected in low amounts. Within the next three days rate of apoptosis in untreated hypoxic cultures cumulated to 85% +/- 11% (p \textless or = 0.001). Specific cytokine (VEGF) patterns also suggest anti-apoptotic strategies of neuronal cells. Remarkably, the administration of MNC showed a noticeable reduction of apoptosis rates to levels of normoxic control cultures (7% +/- 3%; p \textless or = 0.001). In parallel, clustering of administered MNC next to axons and somata of neuronal cells was observed. Furthermore, MNC caused a pronounced increase of chemokines (CCL5; CCL3 and CXCL10).\backslashr\backslashnCONCLUSION\backslashr\backslashnWe established an in vitro model of neuronal hypoxia that affords the possibility to investigate both, apoptotic neuronal cell death and neuroprotective therapies. Here we employed the therapeutic model to study neuroprotective properties of HUCB cells. We hypothesize that the neuroprotective effect of MNC was due to anti-apoptotic mechanisms related to direct cell-cell contacts with injured neuronal cells and distinct changes in neuroprotective, inflammatory cytokines as well as to the upregulation of chemokines within the co-cultures. BACKGROUND One of the most promising options for treatment of stroke using adult stem cells are human umbilical cord blood (HUCB) cells that were already approved for therapeutic efficacy in vivo. However, complexity of animal models has thus far limited the understanding of beneficial cellular mechanisms. To address the influence of HUCB cells on neuronal tissue after stroke we established and employed a human in vitro model of neuronal hypoxia using fully differentiated vulnerable SH-SY5Y cells. These cells were incubated under an oxygen-reduced atmosphere (O2\textless 1%) for 48 hours. Subsequently, HUCB mononuclear cells (MNC) were added to post-hypoxic neuronal cultures. These cultures were characterized regarding to the development of apoptosis and necrosis over three days. Based on this we investigated the therapeutic influence of HUCB MNC on the progression of apoptotic cell death. The impact of HUCB cells and hypoxia on secretion of neuroprotective and inflammatory cytokines, chemokines and expression of adhesion molecules was proved. RESULTS Hypoxic cultivation of neurons initially induced a rate of 26% +/- 13% of apoptosis. Hypoxia also caused an enhanced expression of Caspase-3 and cleaved poly(ADP-ribose) polymerase (PARP). Necrosis was only detected in low amounts. Within the next three days rate of apoptosis in untreated hypoxic cultures cumulated to 85% +/- 11% (p \textless or = 0.001). Specific cytokine (VEGF) patterns also suggest anti-apoptotic strategies of neuronal cells. Remarkably, the administration of MNC showed a noticeable reduction of apoptosis rates to levels of normoxic control cultures (7% +/- 3%; p \textless or = 0.001). In parallel, clustering of administered MNC next to axons and somata of neuronal cells was observed. Furthermore, MNC caused a pronounced increase of chemokines (CCL5; CCL3 and CXCL10). CONCLUSION We established an in vitro model of neuronal hypoxia that affords the possibility to investigate both, apoptotic neuronal cell death and neuroprotective therapies. Here we employed the therapeutic model to study neuroprotective properties of HUCB cells. We hypothesize that the neuroprotective effect of MNC was due to anti-apoptotic mechanisms related to direct cell-cell contacts with injured neuronal cells and distinct changes in neuroprotective, inflammatory cytokines as well as to the upregulation of chemokines within the co-cultures.

Authors: Susann Hau, Doreen M. Reich, Markus Scholz, Wilfried Naumann, Frank Emmrich, Manja Kamprad, Johannes Boltze

Date Published: 2008

Publication Type: Journal article

Impact of chess training on mathematics performance and concentration ability of children with learning disabilities
Genetical Statistics and Systems Biology

Abstract

Not specified

Authors: Markus Scholz, Harald Niesch, Olaf Steffen, Baerbel Ernst, Markus Loeffler, Evelin Witruk, Hans Schwarz

Date Published: 2008

Publication Type: Journal article

Beneficial effects of a 4-week exercise program on plasma concentrations of adhesion molecules
Genetical Statistics and Systems Biology

Abstract

Not specified

Authors: Anke Tönjes, Markus Scholz, Mathias Fasshauer, Jürgen Kratzsch, Fauci Rassoul, Michael Stumvoll, Matthias Blüher

Date Published: 27th Feb 2007

Publication Type: Journal article

Association of Pro12Ala polymorphism in peroxisome proliferator-activated receptor gamma with Pre-diabetic phenotypes: meta-analysis of 57 studies on nondiabetic individuals
Genetical Statistics and Systems Biology

Abstract (Expand)

OBJECTIVE The provariant of the Pro12Ala polymorphism in peroxisome proliferator-activated receptor (PPAR)gamma has been identified as a risk allele for type 2 diabetes. The purpose of the present study …y was to reveal a significant association with pre-diabetic phenotypes in nondiabetic individuals based on a systematic meta-analysis of all available published evidence. RESEARCH DESIGN AND METHODS We performed a classical meta-analysis of data from approximately 32,000 nondiabetic subjects in 57 studies to assess the effect of the Pro12Ala polymorphism on pre-diabetic traits. RESULTS In the global comparison, there were no differences in BMI, glucose, insulin, or homeostasis model assessment of insulin resistance between the Pro/Pro and X/Ala genotype. However, in the Caucasian subgroup, the X/Ala genotype was associated with significantly increased BMI. In the obese subgroup (BMI \textgreater30 kg/m(2)), fasting glucose (P = 0.041) and insulin resistance (by homeostasis model analysis) (P = 0.020) were significantly greater in the Pro/Pro group. In subjects with the homozygous Ala/Ala genotype, fasting insulin was significantly lower compared with the Pro/Pro genotype (P = 0.040, N(Ala/Ala) = 154). CONCLUSIONS Across all studies, the Pro12Ala polymorphism had no significant effect on diabetes-related traits. Only in selected subgroups, such as Caucasians and obese subjects, did we see an association of the Ala allele with greater BMI and greater insulin sensitivity. This demonstrates the importance for appropriate stratification of analyses by environmental or other genetic factors. Meta-analysis of Ala/Ala homozygotes more clearly demonstrated the association with greater insulin sensitivity of carriers of the Ala allele.

Authors: Anke Tönjes, Markus Scholz, Markus Loeffler, Michael Stumvoll

Date Published: 25th Oct 2006

Publication Type: Journal article

Model-based design of chemotherapeutic regimens that account for heterogeneity in leucopoenia
Genetical Statistics and Systems Biology

Abstract (Expand)

Patients treated with multicycle chemotherapy can exhibit large interindividual heterogeneity of haematotoxicity. We describe how a biomathematical model of human granulopoiesis can be used to design … risk-adapted dose-dense chemotherapies, leading to more similar leucopoenias in the population. Calculations were performed on a large data set for cyclophosphamide/doxorubicin/vincristine/prednisone (CHOP)-like chemotherapies for aggressive non-Hodgkin lymphoma. Age, gender, Eastern Cooperative Oncology Group performance status, lactate dehydrogenase and the degree of leucopoenia within the first therapy cycle were used to stratify patients into groups with different expected severity of leucopoenia. We estimated risk-specific bone marrow toxicities depending on the drug doses administered. These toxicities were used to derive risk-adapted therapy schedules. We determined different doses of cyclophosphamide and additional etoposide for patients treated with CHOP-14. Alternatively, the model predicted that further reductions of cycle duration were feasible in groups with low toxicity. We also used the model to identify appropriate granulocyte colony-stimulating factor (G-CSF) schedules. In conclusion, we present a method to estimate the potential of risk-specific dose adaptation of different cytotoxic drugs in order to design chemotherapy protocols that result in decreased diversity of leucopoenia between patients, to develop dose-escalation strategies in cases of low leucopoenic reaction and to determine optimal G-CSF support.

Authors: Markus Scholz, Christoph Engel, Markus Loeffler

Date Published: 1st Mar 2006

Publication Type: Journal article

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