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)

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: Connell, Professor John and Dominiczak, Professor Anna
• 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 > School of Cardiovascular & Metabolic Health
• 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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Project Code	Award No	Project Name	Principal Investigator	Funder's Name	Funder Ref	Lead Dept
39252	1	Regulation of aldosterone and cortisol synthesis in hypertension and cardiovascular disease	Eleanor Davies	Medical Research Council (MRC)	G0400874	Institute of Cardiovascular and Medical Sciences
39252	2	Regulation of aldosterone and cortisol synthesis in hypertension and cardiovascular disease	Eleanor Davies	Medical Research Council (MRC)	G0400874	Institute of Cardiovascular and Medical Sciences