Common genetic variation near the phospholamban gene is associated with cardiac repolarisation: meta-analysis of three genome-wide association studies.
Nolte IM., Wallace C., Newhouse SJ., Waggott D., Fu J., Soranzo N., Gwilliam R., Deloukas P., Savelieva I., Zheng D., Dalageorgou C., Farrall M., Samani NJ., Connell J., Brown M., Dominiczak A., Lathrop M., Zeggini E., Wain LV., Wellcome Trust Case Control Consortium None., DCCT/EDIC Research Group None., Newton-Cheh C., Eijgelsheim M., Rice K., de Bakker PI., QTGEN consortium None., Pfeufer A., Sanna S., Arking DE., QTSCD consortium None., Asselbergs FW., Spector TD., Carter ND., Jeffery S., Tobin M., Caulfield M., Snieder H., Paterson AD., Munroe PB., Jamshidi Y.
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.