Garnier, Sophie and Harakalova, Magdalena and Weiss, Stefan and Mokry, Michal and Regitz-Zagrosek, Vera and Hengstenberg, Christian and Cappola, Thomas P. and Isnard, Richard and Arbustini, Eloisa and Cook, Stuart A. and van Setten, Jessica and Calis, Jorg J. A. and Hakonarson, Hakon and Morley, Michael P. and Stark, Klaus and Prasad, Sanjay K. and Li, Jin and O'Regan, Declan P. and Grasso, Maurizia and Mueller-Nurasyid, Martina and Meitinger, Thomas and Empana, Jean-Philippe and Strauch, Konstantin and Waldenberger, Melanie and Marguiles, Kenneth B. and Seidman, Christine E. and Kararigas, Georgios and Meder, Benjamin and Haas, Jan and Boutouyrie, Pierre and Lacolley, Patrick and Jouven, Xavier and Erdmann, Jeanette and Blankenberg, Stefan and Wichter, Thomas and Ruppert, Volker and Tavazzi, Luigi and Dubourg, Olivier and Roizes, Gerard and Dorent, Richard and de Groote, Pascal and Fauchier, Laurent and Trochu, Jean-Noel and Aupetit, Jean-Francois and Bilinska, Zofia T. and Germain, Marine and Voelker, Uwe and Hemerich, Daiane and Raji, Ibticem and Bacq-Daian, Delphine and Proust, Carole and Remior, Paloma and Gomez-Bueno, Manuel and Lehnert, Kristin and Maas, Renee and Olaso, Robert and Saripella, Ganapathi Varma and Felix, Stephan B. and McGinn, Steven and Duboscq-Bidot, Laetitia and van Mil, Alain and Besse, Celine and Fontaine, Vincent and Blanche, Helene and Ader, Flavie and Keating, Brendan and Curjol, Angelique and Boland, Anne and Komajda, Michel and Cambien, Francois and Deleuze, Jean-Francois and Doerr, Marcus and Asselbergs, Folkert W. and Villard, Eric and Tregoueet, David-Alexandre and 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. EUROPEAN HEART JOURNAL, 42 (20). pp. 2000-2011. ISSN 0195-668X, 1522-9645
Full text not available from this repository. (Request a copy)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]
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | TAURINE; Dilated cardiomyopathy; Heart failure; GWAS; Imputation; 4C-sequencing; Genetic risk score |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Innere Medizin II Medicine > Institut für Epidemiologie und Präventivmedizin > Lehrstuhl für Genetische Epidemiologie |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 04 Oct 2022 08:20 |
| Last Modified: | 04 Oct 2022 08:20 |
| URI: | https://pred.uni-regensburg.de/id/eprint/48195 |
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