1. Genetic association study identifies HSPB7 as a risk gene for idiopathic dilated cardiomyopathy
- Author
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François Cambien, Anette Richter, Bernhard Maisch, Christa Zollbrecht, Laurence Tiret, Klaus Stark, Christa Meisinger, Jeanette Erdmann, Thomas Meitinger, Jean-Noël Trochu, Marie-Claude Aumont, Wolfgang Koenig, Laurent Fauchier, Arne Schillert, Peter Lichtner, Martina Grassl, Norman Klopp, Jens Baumert, Iris M. Heid, Vera Regitz-Zagrosek, Pascal DeGroote, Inke R. König, Philippe Charron, Patrick Linsel-Nitschke, Thomas Illig, Eric Villard, Roland Hetzer, Ulrike B. Esslinger, Thomas Wichter, Michel Komajda, Christian Hengstenberg, Thomas W. Winkler, Richard Isnard, Wibke Reinhard, H.-Erich Wichmann, Olivier Dubourg, Heribert Schunkert, George Petrov, Cardiovascular Sciences, Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Department of Internal Medicine II, Division of Respirology, University of Regensburg, Regensburg, Germany, Universität Regensburg (UR), Klinik und Poliklinik für Innere Medizin II, Universitätsklinikum Regensburg, WSB Neue Energien Gmbh, Partenaires INRAE, Cardiovascular Genomics, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Génétique, pharmacologie et physiopathologie des maladies cardiovasculaires, CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Génétique épidémiologique et moléculaire des pathologies cardiovasculaires, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR14-Institut National de la Santé et de la Recherche Médicale (INSERM), Génomique cardiovasculaire, Service de cardiologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Département de la Médecine, Université Paris Diderot - Paris 7 (UPD7), Hôpital Ambroise Paré [AP-HP], Institut du thorax, Université de Nantes (UN)-IFR26-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Trousseau [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Philipps Universität Marburg = Philipps University of Marburg, and Universität Osnabrück - Osnabrück University
- Subjects
Male ,Cancer Research ,Linkage disequilibrium ,Cardiovascular Disorders/Heart Failure ,HSP27 Heat-Shock Proteins ,Bioinformatics ,Gastroenterology ,Polymerase Chain Reaction ,Linkage Disequilibrium ,[SHS]Humanities and Social Sciences ,Gene Frequency ,Risk Factors ,Child ,Genetics (clinical) ,Genetics and Genomics/Genetics of Disease ,ComputingMilieux_MISCELLANEOUS ,Aged, 80 and over ,education.field_of_study ,Middle Aged ,Cardiovascular Disorders/Myopathies ,Genetics and Genomics/Gene Discovery ,Female ,Research Article ,Adult ,Cardiomyopathy, Dilated ,medicine.medical_specialty ,Adolescent ,Genotype ,lcsh:QH426-470 ,Population ,Single-nucleotide polymorphism ,Biology ,Genetics and Genomics/Complex Traits ,Polymorphism, Single Nucleotide ,Young Adult ,Internal medicine ,Idiopathic dilated cardiomyopathy ,Genetics ,medicine ,SNP ,Humans ,Genetic Predisposition to Disease ,ddc:610 ,education ,Molecular Biology ,Allele frequency ,Ecology, Evolution, Behavior and Systematics ,Genetic Association Studies ,Genetic association ,Aged ,Sequence Analysis, DNA ,Minor allele frequency ,lcsh:Genetics ,Logistic Models ,Case-Control Studies - Abstract
Dilated cardiomyopathy (DCM) is a structural heart disease with strong genetic background. Monogenic forms of DCM are observed in families with mutations located mostly in genes encoding structural and sarcomeric proteins. However, strong evidence suggests that genetic factors also affect the susceptibility to idiopathic DCM. To identify risk alleles for non-familial forms of DCM, we carried out a case-control association study, genotyping 664 DCM cases and 1,874 population-based healthy controls from Germany using a 50K human cardiovascular disease bead chip covering more than 2,000 genes pre-selected for cardiovascular relevance. After quality control, 30,920 single nucleotide polymorphisms (SNP) were tested for association with the disease by logistic regression adjusted for gender, and results were genomic-control corrected. The analysis revealed a significant association between a SNP in HSPB7 gene (rs1739843, minor allele frequency 39%) and idiopathic DCM (p = 1.06×10−6, OR = 0.67 [95% CI 0.57–0.79] for the minor allele T). Three more SNPs showed p < 2.21×10−5. De novo genotyping of these four SNPs was done in three independent case-control studies of idiopathic DCM. Association between SNP rs1739843 and DCM was significant in all replication samples: Germany (n = 564, n = 981 controls, p = 2.07×10−3, OR = 0.79 [95% CI 0.67–0.92]), France 1 (n = 433 cases, n = 395 controls, p = 3.73×10−3, OR = 0.74 [95% CI 0.60–0.91]), and France 2 (n = 249 cases, n = 380 controls, p = 2.26×10−4, OR = 0.63 [95% CI 0.50–0.81]). The combined analysis of all four studies including a total of n = 1,910 cases and n = 3,630 controls showed highly significant evidence for association between rs1739843 and idiopathic DCM (p = 5.28×10−13, OR = 0.72 [95% CI 0.65–0.78]). None of the other three SNPs showed significant results in the replication stage. This finding of the HSPB7 gene from a genetic search for idiopathic DCM using a large SNP panel underscores the influence of common polymorphisms on DCM susceptibility., Author Summary Dilated cardiomyopathy is a severe disease of the heart muscle and often leads to chronic heart failure, eventually with the consequence of cardiac transplantation. Identification of genetic disease markers in at-risk persons could play an important role in preventive health care. Several mutations in familial forms of the disease are described. Here, we examine the role of common genetic variants on the sporadic form of dilated cardiomyopathy. By screening about 2,000 candidate genes previously related to cardiovascular disease in more than 1,900 cases and 3,600 controls, we show that a polymorphism in the HSPB7 gene (rs1739843) is strongly associated with susceptibility to dilated cardiomyopathy. We also show that the effect on disease risk is present in both German and French cohorts. Therefore, this study is an important step towards revealing insight in the genetic background of the sporadic form of dilated cardiomyopathy.
- Published
- 2010
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