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© 2009 Nolte et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.

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.

Details

Title
Common Genetic Variation Near the Phospholamban Gene Is Associated with Cardiac Repolarisation: Meta-Analysis of Three Genome-Wide Association Studies
Author
Nolte, Ilja M; Wallace, Chris; Newhouse, Stephen J; Waggott, Daryl; Fu, Jingyuan; Soranzo, Nicole; Gwilliam, Rhian; Deloukas, Panos; Savelieva, Irina; Zheng, Dongling; Dalageorgou, Chrysoula; Farrall, Martin; Samani, Nilesh J; Connell, John; Brown, Morris; Dominiczak, Anna; Lathrop, Mark; Zeggini, Eleftheria; Wain, Louise V; for the The Wellcome Trust Case Control Consortium; The DCCT/EDIC Research Group 1 ; Newton-Cheh, Christopher; Eijgelsheim, Mark; Rice, Kenneth; Paul I W de Bakker; for the QTGEN consortium; Pfeufer, Arne; Sanna, Serena; Arking, Dan E; for the QTSCD consortium; Asselbergs, Folkert W; Spector, Tim D; Carter, Nicholas D; Jeffery, Steve; Tobin, Martin; Caulfield, Mark; Snieder, Harold; Paterson, Andrew D; Munroe, Patricia B; Jamshidi, Yalda

 The DCCT/EDIC Research Group 
First page
e6138
Section
Research Article
Publication year
2009
Publication date
Jul 2009
Publisher
Public Library of Science
e-ISSN
19326203
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
1290697041
Copyright
© 2009 Nolte et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.