Modification of PM-Mediated Arrhythmogenesis in Populations

描述(申请人提供)：这项拟议的研究考察了由常见基因变异引起的颗粒物(PM)空气污染致心律失常效应的易感性。它的理论基础来自于环境中PM空气污染浓度和急性冠心病(CHD)事件之间已建立的、但不同种类的联系，这是一种广泛但鲜为人知的对公众健康的威胁。它的重点是静息的、标准的十二导联心电测量，一方面与周围的PM浓度有关，另一方面与急性冠心病事件有关。它将以最佳方式利用来自妇女健康倡议临床试验(WHI CT)、SNP健康协会资源项目(SHARE，NHLBI-PB-2006-091)、WHI心律失常发生的环境流行病学(5-R01-ES012238)、社区动脉粥样硬化风险(ARIC)研究以及使用基因组学和流行病学的人口结构(PAGE)联合体的基因组、环境和心电图数据。具体地说，它将检查1987至2004年间评估的七个不同亚群中的心率变异性、心室复极、心肌缺血和心室异位。这七个亚群包括：(1)5148名黑人女性，(2)2002名西班牙裔女性，(3)1507名白人女性，在WHI CT中有或没有脑室异位；在ARIC研究中，(4)2615名黑人女性，(5)5989名白人女性，(6)1621名黑人男性和(7)5369名白人男性。亚群1-7将被用来独立地识别在Affymetrix 6.0阵列上分型的大约106个单核苷酸多态(SNP)与在地理编码参与者地址空间内插的日平均环境PM浓度之间的基因与环境的相互作用。SNP的主要影响也将被调查。内部联合资助的分析将得到很好的支持，并针对多重比较进行适当调整。预期的结果将为检查不同种族和性别之间的相关性提供基础。总的来说，他们将促进对PM介导的心律失常的遗传易感性和潜在的病理生理机制的理解，在居住在美国环境保护局(EPA)区域1-10的25,758名具有统一特征的参与者中，这些参与者在种族和地理上具有代表性。这一进展将使人们深入了解可归因于PM的心电图异常的比例，这些异常可以通过建立和遵守更严格的国家环境空气质量标准来减少。 公共卫生相关性：拟议的研究将有效地促进对PM介导的心律失常的遗传易感性和潜在的病理生理机制的理解，该人群居住在美国环境保护局(EPA)区域1-10，具有种族和地理代表性的25,758名统一特征良好的参与者。其理论基础来自于环境颗粒物空气污染水平和急性冠心病事件之间既有但不同的联系，这是一种广泛但鲜为人知的对公众健康的威胁。

DESCRIPTION (provided by applicant): The proposed study examines susceptibility to the arrhythmogenic effects of particulate matter (PM) air pollution contributed by common genetic variation. Its rationale derives from the established, but heterogeneous association between ambient concentrations of PM air pollution and acute coronary heart disease (CHD) events, a widespread, but poorly understood threat to public health. Its focus is on resting, standard twelve-lead ECG measures that have been linked to ambient PM concentrations on the one hand, and to acute CHD events on the other. It will optimally leverage the genomic, environmental and electrocardiographic data from the Women's Health Initiative clinical trial (WHI CT), The SNP Health Association Resource project (SHARe, NHLBI-PB-2006-091), The Environmental Epidemiology of Arrhythmogenesis in WHI (5-R01-ES012238), the Atherosclerosis Risk in Communities (ARIC) study and the Population Architecture using Genomics and Epidemiology (PAGE) consortium. Specifically, it will examine measures of heart rate variability, ventricular repolarization, myocardial ischemia and ventricular ectopy within seven distinct subpopulations evaluated between 1987 and 2004. The seven subpopulations include: (1) 5148 black women, (2) 2002 Hispanic women, and (3) 1507 white women with and 1507 without ventricular ectopy in the WHI CT; and in the ARIC study, (4) 2615 black women, (5) 5989 white women, (6) 1621 black men, and (7) 5369 white men. Subpopulations 1-7 will be used to independently identify gene-by-environment interactions between approximately 106 single nucleotide polymorphisms (SNPs) genotyped on the Affymetrix 6.0 array and daily mean ambient PM concentrations spatially interpolated at geocoded participant addresses. SNP main effects will also be investigated. The intramurally co-funded analyses will be well-powered and appropriately adjusted for multiple comparisons. Anticipated findings will provide a foundation for examining the consistency of associations across race and gender. Collectively, they will advance understanding of genetic susceptibility to and the pathophysiological mechanisms underlying PM-mediated arrhythmogenesis in an ethnically and geographically representative population of 25,758 uniformly well-characterized participants living in U.S. Environmental Protection Agency (EPA) Regions 1-10. The advance will provide insight into the proportion of PM-attributable ECG abnormalities that could be reduced by establishing and complying with stricter National Ambient Air Quality Standards. PUBLIC HEALTH RELEVANCE: The proposed study will efficiently advance understanding of genetic susceptibility to and the pathophysiological mechanisms underlying PM-mediated arrhythmogenesis in an ethnically and geographically representative population of 25,758 uniformly well-characterized participants living in U.S. Environmental Protection Agency (EPA) Regions 1-10. Its rationale derives from the established, but heterogeneous association between ambient levels of particulate matter air pollution and acute coronary heart disease events, a widespread, but poorly understood threat to public health.