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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

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

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

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

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

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

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

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

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

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

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

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

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

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

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