Common genetic variation near the phospholamban gene is associated with cardiac repolarisation: meta-analysis of three genome-wide association studies.

Journal article

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.

Authors: Nolte, I; Wallace, C; Newhouse, S; Waggott, D; Fu, J

• Publication status: Published
• Journal: PloS one
• Volume: 4
• Issue: 7
• Pages: e6138
• Publication date: 2009-01-01
• DOI: 10.1371/journal.pone.0006138
• EISSN: 1932-6203
• ISSN: 1932-6203
• Language: English
• Keywords: Genetic Variation; Heart; Cohort Studies; Humans; Genome-Wide Association Study; Wellcome Trust Case Control Consortium; QTGEN consortium; Calcium-Binding Proteins; QTSCD consortium; Chromosomes, Human, Pair 6; DCCT/EDIC Research Group