; 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-Francois ; Dörr, Marcus ; Asselbergs, Folkert W.
; Villard, Eric ; Trégouët, David-Alexandre ; Charron, Philippe | Dokumentenart: | Artikel | ||||
|---|---|---|---|---|---|
| Titel eines Journals oder einer Zeitschrift: | European Heart Journal | ||||
| Verlag: | Oxford Univ. Press | ||||
| Ort der Veröffentlichung: | OXFORD | ||||
| Band: | 42 | ||||
| Nummer des Zeitschriftenheftes oder des Kapitels: | 20 | ||||
| Seitenbereich: | S. 2000-2011 | ||||
| Datum: | 2021 | ||||
| Institutionen: | Medizin > Lehrstuhl für Innere Medizin II Medizin > Institut für Epidemiologie und Präventivmedizin > Lehrstuhl für Genetische Epidemiologie | ||||
| Identifikationsnummer: |
| ||||
| Stichwörter / Keywords: | Dilated cardiomyopathy; Heart failure; GWAS; Imputation; 4C-sequencing; Genetic risk score | ||||
| Dewey-Dezimal-Klassifikation: | 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin | ||||
| Status: | Veröffentlicht | ||||
| Begutachtet: | Ja, diese Version wurde begutachtet | ||||
| An der Universität Regensburg entstanden: | Zum Teil | ||||
| Dokumenten-ID: | 56763 |
Zusammenfassung
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 ...

Zusammenfassung
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]
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