Arking Dan E, Khera Amit, Xing Chao, Kao W H Linda, Post Wendy, Boerwinkle Eric, Chakravarti Aravinda
McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
PLoS One. 2009;4(1):e4333. doi: 10.1371/journal.pone.0004333. Epub 2009 Jan 30.
Extremes of electrocardiographic QT interval are associated with increased risk for sudden cardiac death (SCD); thus, identification and characterization of genetic variants that modulate QT interval may elucidate the underlying etiology of SCD. Previous studies have revealed an association between a common genetic variant in NOS1AP and QT interval in populations of European ancestry, but this finding has not been extended to other ethnic populations. We sought to characterize the effects of NOS1AP genetic variants on QT interval in the multi-ethnic population-based Dallas Heart Study (DHS, n = 3,072). The SNP most strongly associated with QT interval in previous samples of European ancestry, rs16847548, was the most strongly associated in White (P = 0.005) and Black (P = 3.6 x 10(-5)) participants, with the same direction of effect in Hispanics (P = 0.17), and further showed a significant SNP x sex-interaction (P = 0.03). A second SNP, rs16856785, uncorrelated with rs16847548, was also associated with QT interval in Blacks (P = 0.01), with qualitatively similar results in Whites and Hispanics. In a previously genotyped cohort of 14,107 White individuals drawn from the combined Atherosclerotic Risk in Communities (ARIC) and Cardiovascular Health Study (CHS) cohorts, we validated both the second locus at rs16856785 (P = 7.63 x 10(-8)), as well as the sex-interaction with rs16847548 (P = 8.68 x 10(-6)). These data extend the association of genetic variants in NOS1AP with QT interval to a Black population, with similar trends, though not statistically significant at P<0.05, in Hispanics. In addition, we identify a strong sex-interaction and the presence of a second independent site within NOS1AP associated with the QT interval. These results highlight the consistent and complex role of NOS1AP genetic variants in modulating QT interval.
心电图QT间期的极端情况与心脏性猝死（SCD）风险增加相关；因此，识别和表征调节QT间期的基因变异可能有助于阐明SCD的潜在病因。先前的研究已经揭示了欧洲血统人群中一氧化氮合酶1适配蛋白（NOS1AP）的一种常见基因变异与QT间期之间的关联，但这一发现尚未扩展到其他种族人群。我们试图在基于多民族人群的达拉斯心脏研究（DHS，n = 3072）中表征NOS1AP基因变异对QT间期的影响。在先前欧洲血统样本中与QT间期关联最紧密的单核苷酸多态性（SNP）rs16847548，在白人（P = 0.005）和黑人（P = 3.6×10⁻⁵）参与者中关联最为紧密，在西班牙裔中具有相同的效应方向（P = 0.17），并且进一步显示出显著的SNP×性别交互作用（P = 0.03）。另一个与rs16847548不相关的SNP rs16856785，在黑人中也与QT间期相关（P = 0.01），在白人和西班牙裔中结果定性相似。在一个先前进行基因分型的由社区动脉粥样硬化风险研究（ARIC）和心血管健康研究（CHS）队列合并而来的14107名白人个体的队列中，我们验证了rs16856785处的第二个位点（P = 7.63×10⁻⁸）以及与rs16847548的性别交互作用（P = 8.68×10⁻⁶）。这些数据将NOS1AP基因变异与QT间期的关联扩展到了黑人人群，在西班牙裔中虽趋势相似但在P<0.05时无统计学显著性。此外，我们识别出了一种强烈的性别交互作用以及NOS1AP内与QT间期相关的第二个独立位点的存在。这些结果突出了NOS1AP基因变异在调节QT间期方面持续且复杂的作用。
