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      Genetic Association Study Identifies HSPB7 as a Risk Gene for Idiopathic Dilated Cardiomyopathy

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      1 , 1 , 1 , 2 , 3 , 4 , 5 , 5 , 5 , 5 , 6 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 12 , 13 , 1 , 1 , 14 , 14 ,   14 , 15 , 15 , 15 , 15 , 15 , 16 , 17 , 18 , 18 , 19 , 20 , 20 , 3 , 4 , 15 , 2 , 1 , *
      PLoS Genetics
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          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.

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          Most cited references34

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          Primer3Plus, an enhanced web interface to Primer3

          Here we present Primer3Plus, a new web interface to the popular Primer3 primer design program as an enhanced alternative for the CGI- scripts that come with Primer3. Primer3 consists of a command line program and a web interface. The web interface is one large form showing all of the possible options. This makes the interface powerful, but at the same time confusing for occasional users. Primer3Plus provides an intuitive user interface using present-day web technologies and has been developed in close collaboration with molecular biologists and technicians regularly designing primers. It focuses on the task at hand, and hides detailed settings from the user until these are needed. We also added functionality to automate specific tasks like designing primers for cloning or step-wise sequencing. Settings and designed primer sequences can be stored locally for later use. Primer3Plus supports a range of common sequence formats, such as FASTA. Finally, primers selected by Primer3Plus can be sent to an order form, allowing tight integration into laboratory ordering systems. Moreover, the open architecture of Primer3Plus allows easy expansion or integration of external software packages. The Primer3Plus Perl source code is available under GPL license from SourceForge. Primer3Plus is available at http://www.bioinformatics.nl/primer3plus.
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            A note on exact tests of Hardy-Weinberg equilibrium.

            Deviations from Hardy-Weinberg equilibrium (HWE) can indicate inbreeding, population stratification, and even problems in genotyping. In samples of affected individuals, these deviations can also provide evidence for association. Tests of HWE are commonly performed using a simple chi2 goodness-of-fit test. We show that this chi2 test can have inflated type I error rates, even in relatively large samples (e.g., samples of 1,000 individuals that include approximately 100 copies of the minor allele). On the basis of previous work, we describe exact tests of HWE together with efficient computational methods for their implementation. Our methods adequately control type I error in large and small samples and are computationally efficient. They have been implemented in freely available code that will be useful for quality assessment of genotype data and for the detection of genetic association or population stratification in very large data sets.
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              Dilated cardiomyopathy and heart failure caused by a mutation in phospholamban.

              Molecular etiologies of heart failure, an emerging cardiovascular epidemic affecting 4.7 million Americans and costing 17.8 billion health-care dollars annually, remain poorly understood. Here we report that an inherited human dilated cardiomyopathy with refractory congestive heart failure is caused by a dominant Arg --> Cys missense mutation at residue 9 (R9C) in phospholamban (PLN), a transmembrane phosphoprotein that inhibits the cardiac sarcoplasmic reticular Ca2+-adenosine triphosphatase (SERCA2a) pump. Transgenic PLN(R9C) mice recapitulated human heart failure with premature death. Cellular and biochemical studies revealed that, unlike wild-type PLN, PLN(R9C) did not directly inhibit SERCA2a. Rather, PLN(R9C) trapped protein kinase A (PKA), which blocked PKA-mediated phosphorylation of wild-type PLN and in turn delayed decay of calcium transients in myocytes. These results indicate that myocellular calcium dysregulation can initiate human heart failure-a finding that may lead to therapeutic opportunities.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS Genet
                plos
                plosgen
                PLoS Genetics
                Public Library of Science (San Francisco, USA )
                1553-7390
                1553-7404
                October 2010
                October 2010
                21 October 2010
                : 6
                : 10
                : e1001167
                Affiliations
                [1 ]Klinik und Poliklinik für Innere Medizin II, Universitätsklinikum Regensburg, Regensburg, Germany
                [2 ]Institute for Gender in Medicine, Center for Cardiovascular Research, Charité Campus Mitte, Berlin, Germany
                [3 ]Department of Cardiothoracic and Vascular Surgery, German Heart Institute Berlin, Berlin, Germany
                [4 ]Institute of Epidemiology, Public Health, and Gender Studies, University of Regensburg, Regensburg, Germany
                [5 ]Institut National de la Santé et de la Recherche Médicale (INSERM) UMR-S956, University Pierre et Marie Curie (Paris 6), Institut de Cardiologie, Département de Génétique, AP-HP, Hôpital Pitié-Salpêtrière, Paris, France
                [6 ]Institut National de la Santé et de la Recherche Médicale (INSERM), UMR-S937, University Pierre et Marie Curie (Paris 6), Paris, France
                [7 ]Service de Cardiologie, Hôpital Bichat, AP-HP, Paris, France
                [8 ]Service de Cardiologie, Université de Versailles-Saint Quentin, Hôpital Ambroise Paré, AP-HP, Boulogne, France
                [9 ]Service de Cardiologie, Hôpital Laennec, Nantes, France
                [10 ]Service de Cardiologie B et Laboratoire d'Electrophysiologie Cardiaque, Pole Cœur Thorax Vasculaire Hémostase, Centre Hospitalier Universitaire Trousseau, Tours, France
                [11 ]Service de Cardiologie, Hôpital Cardiologique, Lille, France
                [12 ]Klinik für Innere Medizin I - Kardiologie, Philipps-Universität Marburg, Marburg, Germany
                [13 ]Medizinische Klinik und Poliklinik C, Kardiologie und Angiologie, Universitätsklinikum Münster, Münster, Germany
                [14 ]Medizinische Klinik II, Universität zu Lübeck, Lübeck, Germany
                [15 ]Institute of Epidemiology, HelmholtzZentrum München, München-Neuherberg, Germany
                [16 ]Central Hospital of Augsburg, MONICA/KORA Myocardial Infarction Registry, Augsburg, Germany
                [17 ]Department of Internal Medicine II – Cardiology, University of Ulm Medical Center, Ulm, Germany
                [18 ]Institute of Human Genetics, HelmholtzZentrum München, München-Neuherberg, Germany
                [19 ]Institute of Human Genetics, Klinikum rechts der Isar, Technische Universität München, München, Germany
                [20 ]Institute of Medical Biometry and Statistics, University of Lübeck, Lübeck, Germany
                Georgia Institute of Technology, United States of America
                Author notes

                Conceived and designed the experiments: K Stark, C Hengstenberg. Performed the experiments: K Stark, UB Esslinger, C Zollbrecht, N Klopp, P Lichtner, T Meitinger. Analyzed the data: K Stark, T Winkler, F Cambien, J Baumert, A Schillert, IR König, IM Heid. Contributed reagents/materials/analysis tools: K Stark, G Petrov, M Komajda, R Isnard, P Charron, E Villard, F Cambien, L Tiret, MC Aumont, O Dubourg, JN Trouchu, L Fauchier, P DeGroote, A Richter, B Maisch, T Wichter, M Grassl, H Schunkert, P Linsel-Nitschke, J Erdmann, T Illig, HE Wichmann, C Meisinger, W Koening, R Hetzer, IM Heid, V Regitz-Zagrosek, C Hengstenberg. Wrote the paper: K Stark, UB Esslinger, W Reinhard, IM Heid, V Regitz-Zagrosek, C Hengstenberg.

                Article
                10-PLGE-RA-NV-3727R2
                10.1371/journal.pgen.1001167
                2958814
                20975947
                15130b7c-5e81-451f-8bed-e781b29c22ae
                Stark et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                History
                : 25 July 2010
                : 18 September 2010
                Page count
                Pages: 9
                Categories
                Research Article
                Cardiovascular Disorders/Heart Failure
                Cardiovascular Disorders/Myopathies
                Genetics and Genomics/Complex Traits
                Genetics and Genomics/Gene Discovery
                Genetics and Genomics/Genetics of Disease

                Genetics
                Genetics

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