Common genetic variation near the phospholamban gene is associated with cardiac repolarisation
Meta-analysis of three genome-wide association studies
PLoS ONE , Volume 4 - Issue 7
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<1×10-6. 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 = 1.4×10-83) and the phospholamban (PLN) gene (P = 1.9×10-29). 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.
|This work was funded by the European Commission 7th Framework Programme; grant id fp7/201865 - GENETIC FACTORS FOR OSTEOPOROSIS (GEFOS), This work was funded by the European Commission 7th Framework Programme; grant id fp7/201413 - European Network for Genetic and Genomic Epidemiology (ENGAGE)|
|Organisation||Erasmus MC: University Medical Center Rotterdam|
Nolte, I.M, Wallace, C, Newhouse, S.J, Waggott, D, Fu, J, Soranzo, N, … Jamshidi, Y. (2009). Common genetic variation near the phospholamban gene is associated with cardiac repolarisation. PLoS ONE, 4(7). doi:10.1371/journal.pone.0006138