Common genetic variation near the phospholamban gene is associated with cardiac repolarisation: meta-analysis of three genome-wide association studies.
oleh: Ilja M Nolte, Chris Wallace, Stephen J Newhouse, Daryl Waggott, Jingyuan Fu, Nicole Soranzo, Rhian Gwilliam, Panos Deloukas, Irina Savelieva, Dongling Zheng, Chrysoula Dalageorgou, Martin Farrall, Nilesh J Samani, John Connell, Morris Brown, Anna Dominiczak, Mark Lathrop, Eleftheria Zeggini, Louise V Wain, Wellcome Trust Case Control Consortium, DCCT/EDIC Research Group, Christopher Newton-Cheh, Mark Eijgelsheim, Kenneth Rice, Paul I W de Bakker, QTGEN consortium, Arne Pfeufer, Serena Sanna, Dan E Arking, QTSCD consortium, Folkert W Asselbergs, Tim D Spector, Nicholas D Carter, Steve Jeffery, Martin Tobin, Mark Caulfield, Harold Snieder, Andrew D Paterson, Patricia B Munroe, Yalda Jamshidi
| Format: | Article |
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| Diterbitkan: | Public Library of Science (PLoS) 2009-07-01 |
Deskripsi
To identify loci affecting the electrocardiographic QT interval, a measure of cardiac repolarisation associated with risk of ventricular arrhythmias and sudden cardiac death, we conducted a meta-analysis of three genome-wide association studies (GWAS) including 3,558 subjects from the TwinsUK and BRIGHT cohorts in the UK and the DCCT/EDIC cohort from North America. Five loci were significantly associated with QT interval at P<1x10(-6). To validate these findings we performed an in silico comparison with data from two QT consortia: QTSCD (n = 15,842) and QTGEN (n = 13,685). Analysis confirmed the association between common variants near NOS1AP (P = 1.4x10(-83)) and the phospholamban (PLN) gene (P = 1.9x10(-29)). The most associated SNP near NOS1AP (rs12143842) explains 0.82% variance; the SNP near PLN (rs11153730) explains 0.74% variance of QT interval duration. We found no evidence for interaction between these two SNPs (P = 0.99). PLN is a key regulator of cardiac diastolic function and is involved in regulating intracellular calcium cycling, it has only recently been identified as a susceptibility locus for QT interval. These data offer further mechanistic insights into genetic influence on the QT interval which may predispose to life threatening arrhythmias and sudden cardiac death.