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

Garnier, Sophie; Harakalova, Magdalena; Weiss, Stefan; Mokry, Michal; Regitz-Zagrosek, Vera; Hengstenberg, Christian; Cappola, Thomas P.; Isnard, Richard; Arbustini, Eloisa; Cook, Stuart A.; Setten, Jessica van; Calis, Jorg J. A.; Hakonarson, Hakon; Morley, Michael P.; Stark, Klaus; Prasad, Sanjay K.; Li, Jin; O'Regan, Declan P.; Grasso, Maurizia; Müller-Nurasyid, Martina; Meitinger, Thomas; Empana, Jean-Philippe; Strauch, Konstantin; Waldenberger, Melanie; Marguiles, Kenneth B.; Seidman, Christine E.; Kararigas, Georgios; Meder, Benjamin; Haas, Jan; Boutouyrie, Pierre; Lacolley, Patrick; Jouven, Xavier; Erdmann, Jeanette; Blankenberg, Stefan; Wichter, Thomas; Ruppert, Volker; Tavazzi, Luigi; Dubourg, Olivier; Roizes, Gerard; Dorent, Richard; Groote, Pascal de; Fauchier, Laurent; Trochu, Jean-Noel; Aupetit, Jean-Francois; Bilinska, Zofia T.; Germain, Marine; Völker, Uwe; Hemerich, Daiane; Raji, Ibticem; Bacq-Daian, Delphine; Proust, Carole; Remior, Paloma; Gomez-Bueno, Manuel; Lehnert, Kristin; Maas, Renee; Olaso, Robert; Saripella, Ganapathi Varma; Felix, Stephan B.; McGinn, Steven; Duboscq-Bidot, Laetitia; Mil, Alain van; Besse, Celine; Fontaine, Vincent; Blanche, Helene; Ader, Flavie; Keating, Brendan; Curjol, Angelique; Boland, Anne; Komajda, Michel; Cambien, Francois; Deleuze, Jean-Francois; Dörr, Marcus; Asselbergs, Folkert W.; Villard, Eric; Tregoueet, David-Alexandre und Charron, Philippe (2021): Genome-wide association analysis in dilated cardiomyopathy reveals two new players in systolic heart failure on chromosomes 3p25.1 and 22q11.23. In: European Heart Journal, Bd. 42, Nr. 20: S. 2000-2011

Abstract

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 x 10(-11) and 7.7 x 10(-4) in the discovery and replication steps, respectively] and chromosome 22q11.23 (lead SNP rs7284877, P = 3.3 x 10(-8) and 1.4 x 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. [GRAPHICS]

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 0195-668X
• Sprache: Englisch