PLoS ONE (Jul 2009)

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

  • Ilja M Nolte,
  • Chris Wallace,
  • Stephen J Newhouse,
  • Daryl Waggott,
  • Jingyuan Fu,
  • Nicole Soranzo,
  • Rhian Gwilliam,
  • Panos Deloukas,
  • Irina Savelieva,
  • Dongling Zheng,
  • Chrysoula Dalageorgou,
  • Martin Farrall,
  • Nilesh J Samani,
  • John Connell,
  • Morris Brown,
  • Anna Dominiczak,
  • Mark Lathrop,
  • Eleftheria Zeggini,
  • Louise V Wain,
  • Wellcome Trust Case Control Consortium,
  • DCCT/EDIC Research Group,
  • Christopher Newton-Cheh,
  • Mark Eijgelsheim,
  • Kenneth Rice,
  • Paul I W de Bakker,
  • QTGEN consortium,
  • Arne Pfeufer,
  • Serena Sanna,
  • Dan E Arking,
  • QTSCD consortium,
  • Folkert W Asselbergs,
  • Tim D Spector,
  • Nicholas D Carter,
  • Steve Jeffery,
  • Martin Tobin,
  • Mark Caulfield,
  • Harold Snieder,
  • Andrew D Paterson,
  • Patricia B Munroe,
  • Yalda Jamshidi

DOI
https://doi.org/10.1371/journal.pone.0006138
Journal volume & issue
Vol. 4, no. 7
p. e6138

Abstract

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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<1x10(-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 = 1.4x10(-83)) and the phospholamban (PLN) gene (P = 1.9x10(-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.