Genome-wide association analysis in dilated cardiomyopathy reveals two new players in systolic heart failure on chromosomes 3p25.1 and 22q11.23.
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Garnier Sophie, Harakalova Magdalena, Weiss Stefan, Mokry Michal, Regitz-Zagrosek Vera, Hengstenberg Christian, Cappola Thomas P, Isnard Richard, Arbustini Eloisa, Cook Stuart A, van Setten Jessica, 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 Gérard, Dorent Richard, de Groote Pascal, Fauchier Laurent, Trochu Jean-Noël, Aupetit Jean-François, 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 Laëtitia, van Mil Alain, Besse Céline, Fontaine Vincent, Blanché Hélène, Ader Flavie, Keating Brendan, Curjol Angélique, Boland Anne, Komajda Michel, Cambien François, Deleuze Jean-François, Dörr Marcus, Asselbergs Folkert W, Villard Eric, Trégouët David-Alexandre, Charron Philippe
Аннотация
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.