Abstract 15325: A Common Variant Near the Phospholamban Gene Associates with QT Interval Duration and Heart Rate, and Predicts Risk of Atrial Fibrillation and Sudden Unexpected Death in the General Population
Introduction: Phospholamban plays a key role in calcium signalling in cardiomyocytes by regulating cardiac sarcoplasmic reticulum Ca2+-ATPase. Common variation near PLN, encoding phospholamban, has been associated with heart rate and QT-interval duration in GWAS, and calcium-handling proteins play an important role in atrial fibrillation. One of the strongest hits for QT-interval duration in GWAS is rs11756438 near PLN. We tested the hypothesis that rs11756438 associates with heart rate, QT interval duration, atrial fibrillation and sudden unexpected death in the general population.
Methods: We genotyped rs11756438 in 10,050 individuals from the Copenhagen City Heart Study (CCHS). QT-interval and heart rate were derived from digitalized ECGs from two independent examinations (n=5,221 and 2,725 participants, respectively). The association between genotype and atrial fibrillation (n=1,259) and sudden unexpected death (n=380) was examined prospectively in the CCHS. Information on diagnoses, date of death, and causes of death was collected from 1976 through May 2011 from National Danish registries.
Results: In the first examination, rs11756438 (minor allele frequency: 0.50) was associated with 0.7 (SE:±0.2) beats per minute lower heart rate per minor allele (P for trend=0.02), and 2.1 (SE:±0.6) msec longer QT interval per minor allele (P for trend<0.0001). Similar results were obtained for heart rate corrected QT-intervals. These findings were replicated in the second examination of 2,725 independent participants. Rs11756438 predicted a per allele stepwise decrease in risk of atrial fibrillation (P for trend=0.02) and sudden unexpected death (P for trend=0.05). For homozygotes for the minor allele, hazard ratios for atrial fibrillation and sudden unexpected death were, respectively, 0.82(95% CI: 0.70-0.96) and 0.75(0.56-1.00), compared to non-carriers. These associations were independent of ischemic heart disease (P for trend=0.59).
Conclusion: Genetic variation near PLN associates with heart rate and QT-interval duration, and predicts risk of atrial fibrillation and sudden unexpected death in the general population. This suggests that PLN is an important gene affecting cardiac repolarisation in the general population.
- © 2012 by American Heart Association, Inc.