Abstract
Aims Dilated cardiomyopathy (DCM) is a major cause of heart failure with a high familial recurrence risk. So far, the genetics of DCM remains largely unresolved.We conducted the first genome-wide association study (GWAS) to identify loci contributing to sporadic DCM. Methods and results One thousand one hundred and seventy-nine DCM patients and 1108 controls contributed to the discovery phase. Pools of DNA stratified on disease status, population, age, and gender were constituted and used for testing association of DCM with 517 382 single nucleotide polymorphisms (SNPs). Three DCM-associated SNPs were confirmed by individual genotyping (P < 5.0 10-7), and two of them, rs10927875 and rs2234962, were replicated in independent samples (1165 DCM patients and 1302 controls), with P-values of 0.002 and 0.009, respectively. rs10927875 maps to a region on chromosome 1p36.13 which encompasses several genes among which HSPB7 has been formerly suggested to be implicated in DCM. The second identified locus involves rs2234962, a non-synonymous SNP (c.T757C, p. C151R) located within the sequence of BAG3 on chromosome 10q26. To assess whether coding mutations of BAG3 might cause monogenic forms of the disease, we sequenced BAG3 exons in 168 independent index cases diagnosed with familial DCM and identified four truncating and two missense mutations. Each mutation was heterozygous, present in all genotyped relatives affected by the disease and absent in a control group of 347 healthy individuals, strongly suggesting that these mutations are causing the disease. Conclusion This GWAS identified two loci involved in sporadic DCM, one of them probably implicates BAG3. Our results show that rare mutations in BAG3 contribute to monogenic forms of the disease, while common variant(s) in the same gene are implicated in sporadic DCM.
| Original language | English |
|---|---|
| Journal | European Heart Journal |
| Volume | 32 |
| Issue number | 9 |
| Pages (from-to) | 1065-1076 |
| Number of pages | 12 |
| ISSN | 0195-668X |
| DOIs | |
| Publication status | Published - 01.05.2011 |
Funding
1INSERM, U956, Paris, 75013, France; 2University Paris 6 UPMC, U956, AP-HP Hôpital Pitié-Salpêtrière, Paris 75013, France; 3INSERM UMRS 937, Paris 6 University (UPMC), Paris 75013, France; 4Klinik und Poliklinik für Innere Medizin II, Universitätsklinikum Regensburg, Franz-Josef-Strauss-Allee 11, Regensburg 93053, Germany; 5Klinik für Innere Medizin-Kardiologie UKGM GmbH Standort Marburg Baldingerstrasse, Marburg 35043, Germany; 6Centre for Inherited Cardiovascular Diseases, Academic Hospital IRCCS Foundation Policlinico San Matteo, Pavia, Italy; 7Medizinische Klinik und Poliklinik für Innere Medizin C, Kardiologie und Angiologie, Universitätsklinikum Münster, Albert-Schweitzer-Straße 33, Münster 48149, Germany; 8Université de Versailles-Saint Quentin, Hôpital Ambroise Paré, AP-HP, Boulogne 92100, France; 9GVM Hospitals of Care and Research, Cotignola, Italy; 10Service de Cardiologie, Hôpital Bichat, Paris 75018, France;11Service de Cardiologie, Hôpital Cardiologique, Lille, France;12Service de Cardiologie, Centre Hospitalier Universitaire Trousseau, Tours 37044, France; 13INSERM UMR915, l’institut du thorax, Nantes, France; 14CHU Nantes, Service de Cardiologie, Nantes F-44000, France; 15Service de Cardiologie, CHU Nice, Nice, France; 16Département de pathologie cardiovasculaire, Hôpital Saint-Joseph-Saint-Luc, Lyon, France; 17Universität zu Lübeck, Medizinische Klinik II, Lübeck 23538, Germany; 18Deutsches Herzzentrum Berlin, Augustenburger Platz 1, Berlin 13353, Germany; 19Medical Research Council Clinical Science Centre, Faculty of Medicine, Imperial College London, Hammersmith Hospital, London, UK; 20Heart Science Centre, National Heart and Lung Institute, Imperial College, Harefield UB9 6JH, UK; 21NIHR Cardiovascular Biomedical Research Unit, Royal Brompton and Harefield NHS Foundation Trust, Sydney Street, London SW3 6NP, UK; 22Institute for Gender in Medicine, Center for Cardiovascular Research, Charité Campus Mitte, Berlin, Germany; 23Faculdade de Medicina de Lisboa, Clínica Universitária de Cardiologia, Portugal; 24Department of Public Health and Clinical Medicine/Medicine, Umeå University, Sweden; 25Servicio de Cardiología, Hospital Vall d’Hebron, Barcelona 08035, Spain; 26Department of Cardiology, University of Hull, UK; 27Service de Cardiologie, CHU Tenon, Paris, France; 28Institut de Génétique Humaine, UPR 1142, CNRS, Montpellier, France; 29Medizinische Klinik und Poliklinik, Johannes-Gutenberg Universität Mainz, Universitätsmedizin, Mainz, Germany; 30Department of Cardiovascular Sciences, University of Leicester, and Leicester NIHR Biomedical Research Unit in Cardiovascular Disease, Glenfield Hospital, Leicester LE3 9QP, UK; and 31P3S postgenomics platform, Paris, France This work was supported by grants from Assistance Publique—Hôpitaux de Paris (PHRC programme hospitalier de recherche clinique AOM04141 & AOM95082), the ‘Fondation LEDUCQ’ (Eurogene Heart Failure network and CAERUS network), the Société Franc¸aise de Cardi-ologie/Fédération Franc¸aise de Cardiologie (2006), the CONNY-MAEVA charitable foundation. The GWAS was supported by the French ‘Agence Nationale pour la Recherche’ (ANR Project ANR-06-BLAN-0264 CSD 8, ‘POOLCA’) and the European Union/FP7 (grant 241924; INHERITANCE). UK replication study was supported by UK National Institute for Health Research Biomedical Research Unit and Biomedical Research Centre funding, the British Heart Foundation, the ‘Fondation LEDUCQ’, and the Medical Research Council UK. The UK Blood Services collection of Common Controls (UKBS collection), part of the Wellcome Trust Case-Control Consortium, was funded by the Wellcome Trust (076113/C104/Z), and the Juvenile Diabetes Research Foundation (WT06l858). The German replication study was supported by the EU (Eugeneheart, IP 01883), the University Hospital of Regensburg and the German Research Foundation (DFG).
