Genome-wide association analysis in dilated cardiomyopathy reveals two new players in systolic heart failure on chromosomes 3p25.1 and 22q11.23.

Autor:	Garnier S; Sorbonne Université, INSERM, UMR-S1166, Research Unit on Cardiovascular Disorders, Metabolism and Nutrition, Team Genomics & Pathophysiology of Cardiovascular Diseases, Paris 75013, France.; ICAN Institute for Cardiometabolism and Nutrition, Paris 75013, France., Harakalova M; Department of Cardiology, Division Heart & Lungs, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.; Regenerative Medicine Center, University Medical Center Utrecht, Utrecht, the Netherlands., Weiss S; Interfaculty Institute for Genetics and Functional Genomics, Department of Functional Genomics, University Medicine Greifswald, Greifswald, Germany.; DZHK (German Centre for Cardiovascular Research), partner site Greifswald, Greifswald, Germany., Mokry M; Department of Cardiology, Division Heart & Lungs, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.; Laboratory of Clinical Chemistry and Haematology, University Medical Center, Heidelberglaan 100, Utrecht, the Netherlands.; Laboratory of Experimental Cardiology, University Medical Center Utrecht, Heidelberglaan 100, Utrecht, the Netherlands., Regitz-Zagrosek V; Institute of Gender in Medicine and Center for Cardiovascular Research, Charite University Hospital, Berlin, Germany.; DZHK (German Center for Cardiovascular Research), Berlin, Germany., Hengstenberg C; Department of Internal Medicine, Division of Cardiology, Medical University of Vienna, Austria.; Department of Internal Medicine, Medical University of Regensburg, Germany., Cappola TP; Penn Cardiovascular Institute and Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA., Isnard R; Sorbonne Université, INSERM, UMR-S1166, Research Unit on Cardiovascular Disorders, Metabolism and Nutrition, Team Genomics & Pathophysiology of Cardiovascular Diseases, Paris 75013, France.; ICAN Institute for Cardiometabolism and Nutrition, Paris 75013, France.; Cardiology Department, APHP, Pitié-Salpêtrière Hospital, Paris, France., Arbustini E; IRCCS Fondazione Policlinico San Matteo, Pavia, Italy., Cook SA; National Heart and Lung Institute, Imperial College London, London, UK.; National Heart Centre Singapore, Singapore.; Duke-NUS, Singapore., van Setten J; Department of Cardiology, Division Heart & Lungs, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands., Calis JJA; Department of Cardiology, Division Heart & Lungs, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.; Regenerative Medicine Center, University Medical Center Utrecht, Utrecht, the Netherlands., Hakonarson H; Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA, USA., Morley MP; Penn Cardiovascular Institute and Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA., Stark K; Department of Genetic Epidemiology, University of Regensburg, Regensburg, Germany., Prasad SK; National Heart Centre Singapore, Singapore.; Royal Brompton Hospital, London, UK., Li J; Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA, USA., O'Regan DP; Medical Research Council Clinical Sciences Centre, Faculty of Medicine, Imperial College London, South Kensington Campus, London SW7 2AZ, UK., Grasso M; Centre for Inherited Cardiovascular Diseases-IRCCS Fondazione Policlinico San Matteo, Pavia, Italy., Müller-Nurasyid M; Institute of Genetic Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.; IBE, Faculty of Medicine, LMU Munich, Germany.; Department of Internal Medicine I (Cardiology), Hospital of the Ludwig-Maximilians-University (LMU) Munich, Munich, Germany., Meitinger T; Institute of Genetic Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.; IBE, Faculty of Medicine, LMU Munich, Germany.; Institute of Human Genetics, Klinikum rechts der Isar, Technische Universität München, Munich, Germany., Empana JP; Université de Paris, INSERM, UMR-S970, Integrative Epidemiology of cardiovascular disease, Paris, France., Strauch K; Institute of Genetic Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.; IBE, Faculty of Medicine, LMU Munich, Germany.; Institute of Medical Biostatistics, Epidemiology and Informatics (IMBEI), University Medical Center, Johannes Gutenberg University, Mainz 55101, Germany., Waldenberger M; Research unit of Molecular Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.; DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany., Marguiles KB; Penn Cardiovascular Institute and Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA., Seidman CE; Department of Medicine and Genetics Harvard Medical School, Boston, MA, USA.; Brigham & Women's Cardiovascular Genetics Center, Boston, MA, USA., Kararigas G; Department of Physiology, Faculty of Medicine, University of Iceland, Vatnsmýrarvegur 16, 101 Reykjavík, Iceland., Meder B; Institute for Cardiomyopathies Heidelberg, Heidelberg University, Germany.; Stanford Genome Technology Center, Department of Genetics, Stanford Medical School, CA, USA., Haas J; Institute for Cardiomyopathies Heidelberg, Heidelberg University, Germany., Boutouyrie P; Université de Paris, INSERM, UMR-S970, Integrative Epidemiology of cardiovascular disease, Paris, France.; Cardiology Department, APHP, Georges Pompidou European Hospital, Paris, France., Lacolley P; INSERM U1116, Faculté de Médecine, Vandoeuvre-les-Nancy, France., Jouven X; Université de Paris, INSERM, UMR-S970, Integrative Epidemiology of cardiovascular disease, Paris, France.; Cardiology Department, APHP, Georges Pompidou European Hospital, Paris, France., Erdmann J; Medizinische Klinik und Poliklinik, Universitätsmedizin der Johannes-Gutenberg Universität Mainz, Mainz, Germany., Blankenberg S; Medizinische Klinik II, Universität Lübeck, Lübeck, Germany., Wichter T; Dept. of Cardiology and Angiology, Niels-Stensen-Kliniken Marienhospital Osnabrück, Heart Centre Osnabrück/Bad Rothenfelde, Osnabrück 49074, Germany., Ruppert V; Klinik für Innere Medizin-Kardiologie UKGM GmbH Standort Marburg Baldingerstrasse, Marburg, Germany., Tavazzi L; Maria Cecilia Hospital, GVM Care and Research, Cotignola, Italy., Dubourg O; Université de Versailles-Saint Quentin, Hôpital Ambroise Paré, AP-HP, Boulogne, France., Roizes G; Institut de Génétique Humaine, UPR 1142, CNRS, Montpellier, France., Dorent R; Service de Cardiologie, CHU Tenon, Paris, France., de Groote P; Service de Cardiologie, Hôpital Cardiologique, Lille, France., Fauchier L; Service de Cardiologie, Centre Hospitalier Universitaire Trousseau, Tours, France., Trochu JN; Université de Nantes, CHU Nantes, CNRS, INSERM, l'institut du thorax, Nantes 44000, France., Aupetit JF; Département de pathologie cardiovasculaire, Hôpital Saint-Joseph-Saint-Luc, Lyon, France., Bilinska ZT; Unit for Screening Studies in Inherited Cardiovascular Diseases, National Institute of Cardiology, Warsaw, Poland., Germain M; Univ. Bordeaux, INSERM, BPH, U1219, Bordeaux 33000, France., Völker U; Interfaculty Institute for Genetics and Functional Genomics, Department of Functional Genomics, University Medicine Greifswald, Greifswald, Germany.; DZHK (German Centre for Cardiovascular Research), partner site Greifswald, Greifswald, Germany., Hemerich D; Department of Cardiology, Division Heart & Lungs, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands., Raji I; AP-HP, Département de Génétique, Centre de Référence Maladies Cardiaques Héréditaires, Hôpital Pitié-Salpêtrière, Paris, France., Bacq-Daian D; Centre National de Recherche en Génomique Humaine (CNRGH), Institut de Biologie François Jacob, CEA, Université Paris-Saclay, Evry 91057, France.; Laboratory of Excellence GENMED (Medical Genomics)., Proust C; Univ. Bordeaux, INSERM, BPH, U1219, Bordeaux 33000, France., Remior P; Department of Cardiology, Hospital Universitario Puerta de Hierro, CIBERCV, Madrid, Spain., Gomez-Bueno M; Department of Cardiology, Hospital Universitario Puerta de Hierro, CIBERCV, Madrid, Spain., Lehnert K; DZHK (German Centre for Cardiovascular Research), partner site Greifswald, Greifswald, Germany.; Department of Internal Medicine B, University Medicine Greifswald, Greifswald, Germany., Maas R; Department of Cardiology, Division Heart & Lungs, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.; Regenerative Medicine Center, University Medical Center Utrecht, Utrecht, the Netherlands., Olaso R; Centre National de Recherche en Génomique Humaine (CNRGH), Institut de Biologie François Jacob, CEA, Université Paris-Saclay, Evry 91057, France.; Laboratory of Excellence GENMED (Medical Genomics)., Saripella GV; Sorbonne Université, INSERM, UMR-S1166, Research Unit on Cardiovascular Disorders, Metabolism and Nutrition, Team Genomics & Pathophysiology of Cardiovascular Diseases, Paris 75013, France.; SLU Bioinformatics Infrastructure (SLUBI), PlantLink, Department of Plant Breeding, Swedish University of Agricultural Sciences, Almas Allé 8, 750 07 Uppsala, Sweden., Felix SB; DZHK (German Centre for Cardiovascular Research), partner site Greifswald, Greifswald, Germany.; Department of Internal Medicine B, University Medicine Greifswald, Greifswald, Germany., McGinn S; Centre National de Recherche en Génomique Humaine (CNRGH), Institut de Biologie François Jacob, CEA, Université Paris-Saclay, Evry 91057, France.; Laboratory of Excellence GENMED (Medical Genomics)., Duboscq-Bidot L; Sorbonne Université, INSERM, UMR-S1166, Research Unit on Cardiovascular Disorders, Metabolism and Nutrition, Team Genomics & Pathophysiology of Cardiovascular Diseases, Paris 75013, France.; ICAN Institute for Cardiometabolism and Nutrition, Paris 75013, France., van Mil A; Department of Cardiology, Division Heart & Lungs, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.; Regenerative Medicine Center, University Medical Center Utrecht, Utrecht, the Netherlands., Besse C; Centre National de Recherche en Génomique Humaine (CNRGH), Institut de Biologie François Jacob, CEA, Université Paris-Saclay, Evry 91057, France.; Laboratory of Excellence GENMED (Medical Genomics)., Fontaine V; Sorbonne Université, INSERM, UMR-S1166, Research Unit on Cardiovascular Disorders, Metabolism and Nutrition, Team Genomics & Pathophysiology of Cardiovascular Diseases, Paris 75013, France.; ICAN Institute for Cardiometabolism and Nutrition, Paris 75013, France., Blanché H; Laboratory of Excellence GENMED (Medical Genomics).; Centre d'Etude du Polymorphisme Humain, Fondation Jean Dausset, Paris, France., Ader F; Sorbonne Université, INSERM, UMR-S1166, Research Unit on Cardiovascular Disorders, Metabolism and Nutrition, Team Genomics & Pathophysiology of Cardiovascular Diseases, Paris 75013, France.; APHP, UF Cardiogénétique et Myogénétique, service de Biochimie métabolique, Hôpital universitaire Pitié-Salpêtrière Paris, France.; Faculté de Pharmacie Paris Descartes, Département 3, Paris 75006, France., Keating B; Division of Transplantation, Department of Surgery, University of Pennsylvania, Philadelphia, PA, USA., Curjol A; AP-HP, Département de Génétique, Centre de Référence Maladies Cardiaques Héréditaires, Hôpital Pitié-Salpêtrière, Paris, France., Boland A; Centre National de Recherche en Génomique Humaine (CNRGH), Institut de Biologie François Jacob, CEA, Université Paris-Saclay, Evry 91057, France.; Laboratory of Excellence GENMED (Medical Genomics)., Komajda M; Sorbonne Université, INSERM, UMR-S1166, Research Unit on Cardiovascular Disorders, Metabolism and Nutrition, Team Genomics & Pathophysiology of Cardiovascular Diseases, Paris 75013, France.; ICAN Institute for Cardiometabolism and Nutrition, Paris 75013, France.; Cardiology Department, Groupe Hospitalier Paris Saint Joseph, Paris, France., Cambien F; Univ. Bordeaux, INSERM, BPH, U1219, Bordeaux 33000, France., Deleuze JF; Centre National de Recherche en Génomique Humaine (CNRGH), Institut de Biologie François Jacob, CEA, Université Paris-Saclay, Evry 91057, France.; Laboratory of Excellence GENMED (Medical Genomics).; Centre d'Etude du Polymorphisme Humain, Fondation Jean Dausset, Paris, France., Dörr M; DZHK (German Centre for Cardiovascular Research), partner site Greifswald, Greifswald, Germany.; Department of Internal Medicine B, University Medicine Greifswald, Greifswald, Germany., Asselbergs FW; Department of Cardiology, Division Heart & Lungs, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.; Institute of Cardiovascular Science, Faculty of Population Health Sciences, University College London, London, UK.; Health Data Research UK and Institute of Health Informatics, University College London, London, UK., Villard E; Sorbonne Université, INSERM, UMR-S1166, Research Unit on Cardiovascular Disorders, Metabolism and Nutrition, Team Genomics & Pathophysiology of Cardiovascular Diseases, Paris 75013, France.; ICAN Institute for Cardiometabolism and Nutrition, Paris 75013, France., Trégouët DA; Univ. Bordeaux, INSERM, BPH, U1219, Bordeaux 33000, France.; Laboratory of Excellence GENMED (Medical Genomics)., Charron P; Sorbonne Université, INSERM, UMR-S1166, Research Unit on Cardiovascular Disorders, Metabolism and Nutrition, Team Genomics & Pathophysiology of Cardiovascular Diseases, Paris 75013, France.; ICAN Institute for Cardiometabolism and Nutrition, Paris 75013, France.; Cardiology Department, APHP, Pitié-Salpêtrière Hospital, Paris, France.; AP-HP, Département de Génétique, Centre de Référence Maladies Cardiaques Héréditaires, Hôpital Pitié-Salpêtrière, Paris, France.
Jazyk:	angličtina
Zdroj:	European heart journal [Eur Heart J] 2021 May 21; Vol. 42 (20), pp. 2000-2011.
DOI:	10.1093/eurheartj/ehab030
Abstrakt:	Aims: Our objective was to better understand the genetic bases of dilated cardiomyopathy (DCM), a leading cause of systolic heart failure. Methods and Results: We conducted the largest genome-wide association study performed so far in DCM, with 2719 cases and 4440 controls in the discovery population. We identified and replicated two new DCM-associated loci on chromosome 3p25.1 [lead single-nucleotide polymorphism (SNP) rs62232870, P = 8.7 × 10-11 and 7.7 × 10-4 in the discovery and replication steps, respectively] and chromosome 22q11.23 (lead SNP rs7284877, P = 3.3 × 10-8 and 1.4 × 10-3 in the discovery and replication steps, respectively), while confirming two previously identified DCM loci on chromosomes 10 and 1, BAG3 and HSPB7. A genetic risk score constructed from the number of risk alleles at these four DCM loci revealed a 3-fold increased risk of DCM for individuals with 8 risk alleles compared to individuals with 5 risk alleles (median of the referral population). In silico annotation and functional 4C-sequencing analyses on iPSC-derived cardiomyocytes identify SLC6A6 as the most likely DCM gene at the 3p25.1 locus. This gene encodes a taurine transporter whose involvement in myocardial dysfunction and DCM is supported by numerous observations in humans and animals. At the 22q11.23 locus, in silico and data mining annotations, and to a lesser extent functional analysis, strongly suggest SMARCB1 as the candidate culprit gene. Conclusion: This study provides a better understanding of the genetic architecture of DCM and sheds light on novel biological pathways underlying heart failure. (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.)
Databáze:	MEDLINE
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