Modification of PM-Mediated Arrhythmogenesis in Populations

描述（由申请人提供）：拟议的研究考察了由常见遗传变异引起的颗粒物（PM）空气污染的易感性。其基本原理源于环境中PM空气污染浓度与急性冠状动脉心脏病（CHD）事件之间的既定但异质性关联，这是一种广泛但对公众健康知之甚少的威胁。它的重点是静息，标准的十二导联心电图测量，一方面与环境PM浓度有关，另一方面与急性冠心病事件有关。它将充分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）研究和使用基因组学和流行病学（PAGE）联盟的人口结构的基因组、环境和心电图数据。具体来说，它将检查1987年至2004年间评估的七个不同亚群的心率变异性、心室复极、心肌缺血和心室异位的测量。7个亚群包括：(1)5148名黑人妇女，(2)2002名西班牙裔妇女，(3)1507名白人妇女，WHI CT显示有和没有室性异位；在ARIC的研究中，(4)2615名黑人女性，(5)5989名白人女性，(6)1621名黑人男性，(7)5369名白人男性。亚群1-7将被用来独立鉴定大约106个单核苷酸多态性（snp）在Affymetrix 6.0阵列上的基因分型与在地理编码的参与者地址上空间插值的每日平均环境PM浓度之间的基因-环境相互作用。SNP的主要影响也将被研究。内部共同资助的分析将得到充分的支持，并对多重比较进行适当调整。预期的结果将为检查跨种族和性别的关联的一致性提供基础。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病理生理机制的理解，这些研究对象是居住在美国环境保护署（EPA）区域1-10的具有种族和地理代表性的25,758名统一特征的参与者。这一进展将深入了解可通过建立和遵守更严格的国家环境空气质量标准来减少由pm引起的ECG异常的比例。

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.