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

Nolte, I. M. et al. (2009) Common genetic variation near the phospholamban gene is associated with cardiac repolarisation: meta-analysis of three genome-wide association studies. PLoS ONE, 4(7), e6138. (doi:10.1371/journal.pone.0006138)

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Publisher's URL: http://dx.doi.org/10.1371/journal.pone.0006138

Abstract

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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Dominiczak, Professor Anna and Connell, Professor John
Authors: Nolte, I. M., Wallace, C., Newhouse, S. J., Waggott, D., Fu, J., Soranzo, N., Gwilliam, R., Deloukas, P., Savelieva, I., Zheng, D., Dalageorgou, C., Farrall, M., Samani, N. J., Connell, J., Brown, M., Dominiczak, A., Lathrop, M., Zeggini, E., Wain, L. V., Newton-Cheh, C., Eijgelsheim, M., Rice, K., de Bakker, P. I.W., Pfeufer, A., Sanna, S., Arking, D. E., Asselbergs, F. W., Spector, T. D., Carter, N. D., Jeffery, S. J., Tobin, M., Caulfield, M., Snieder, H., Paterson, A. D., Munroe, P. B., and Jamshidi, Y.
College/School:College of Medical Veterinary and Life Sciences > School of Medicine, Dentistry & Nursing
College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
Journal Name:PLoS ONE
Publisher:Public Library of Science
ISSN:1932-6203
ISSN (Online):1932-6203
Published Online:09 January 2009
Copyright Holders:Copyright © 2009 Public Library of Science
First Published:First published in PLoS ONE 4(7):e6138
Publisher Policy:Reproduced in accordance with the copyright policy of the publisher
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392521Regulation of aldosterone and cortisol synthesis in hypertension and cardiovascular diseaseEleanor DaviesMedical Research Council (MRC)G0400874/71954Institute of Cardiovascular and Medical Sciences
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