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, Newton-Cheh Christopher, Eijgelsheim Mark, Rice Kenneth, de Bakker Paul I W, Pfeufer Arne, Sanna Serena, Arking Dan E, 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
Unit of Genetic Epidemiology and Bioinformatics, Department of Epidemiology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
PLoS One. 2009 Jul 9;4(7):e6138. doi: 10.1371/journal.pone.0006138.
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.
为了确定影响心电图QT间期（一种与室性心律失常和心源性猝死风险相关的心脏复极指标）的基因座，我们对三项全基因组关联研究（GWAS）进行了荟萃分析，这些研究包括来自英国的双胞胎英国队列和BRIGHT队列的3558名受试者以及来自北美的DCCT/EDIC队列。五个基因座与QT间期显著相关，P<1×10⁻⁶。为了验证这些发现，我们与两个QT研究联盟的数据进行了电子比较：QTSCD（n = 15842）和QTGEN（n = 13685）。分析证实了NOS1AP附近的常见变异（P = 1.4×10⁻⁸³）与受磷蛋白（PLN）基因（P = 1.9×10⁻²⁹）之间的关联。NOS1AP附近最相关的单核苷酸多态性（SNP，rs12143842）解释了0.82%的变异；PLN附近的SNP（rs11153730）解释了QT间期持续时间0.74%的变异。我们没有发现这两个SNP之间存在相互作用的证据（P = 0.99）。PLN是心脏舒张功能的关键调节因子，参与调节细胞内钙循环，直到最近才被确定为QT间期的易感基因座。这些数据为基因对QT间期的影响提供了进一步的机制性见解，QT间期可能易引发危及生命的心律失常和心源性猝死。
