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188 Publications visible to you, out of a total of 188
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

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

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

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

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

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

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

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

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

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

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

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

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

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

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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

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

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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

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

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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

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

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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

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

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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

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

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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

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

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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

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

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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

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

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

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

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

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

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

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

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