Epigenetic Mechanisms of PM-Mediated CVD Risk

描述（由申请人提供）：流行病学研究将暴露于环境颗粒物（PM）空气污染与亚临床和临床心血管疾病联系起来 （CVD）。尽管PM吸入也与血液中炎症、氧化、内皮、代谢和凝血生物标志物的增加有关，但生物标志物的发现和对在人群中产生这种影响的分子机制的理解仍然不完整。我们和其他人一直发现，PM暴露与外周血白细胞DNA中测量的全局和基因特异性甲基化改变有关，这是一种控制基因表达的环境诱导和动态表观遗传机制。白细胞和其他组织中的DNA甲基化也与CVD相关，暗示它是介导环境暴露的心血管效应的主要分子机制。然而，很少有研究探讨PM空气污染的表观遗传学。那些倾向于在环境同质的单一城市白色男性人群中进行的候选基因DNA甲基化的动力不足，不可复制，横断面分析，而不关注能够影响甲基化的其他因素，进而影响CVD风险。因此，我们建议进行一项两阶段的纵向研究，研究PM空气污染，DNA甲基化和CVD危险因素之间的关联，这些因素是在考试地点和种族分层的独立子集中进行的，随机选择了大约4，300名妇女健康倡议临床试验（WHI CT）参与者的6%少数人群，这些参与者进行了空腹抽血和静息，标准，从1993年到2004年，每隔三年重复一次十二导联心电图（ECG）。第一阶段将集中于对来自800名参与者的1999-2001年血液样本中的> 450，000个对PM潜在敏感的DNA甲基化位点的询问、发现和排序。在1993-2004年从剩余的3,500名参与者中连续收集的多达三份血液样本中，第二阶段将集中于第一阶段确定的10个最PM敏感的DNA甲基化位点的纵向验证，PM和这些位点的DNA甲基化之间的时间关系，以及位点特异性DNA甲基化，CVD危险因素和CVD之间的时间关系。拟定的表观遗传学数据分析将在表型组学框架内进行，并针对祖先混合物和多重比较进行充分的动力学和适当的调整。将在ARIC和NAS队列中对结果进行外部验证。概括性的发现将促进对表观遗传机制的理解，以及识别绝经前和绝经后女性、年轻黑人和老年白色男性对PM介导的CVD风险的易感性的生物标志物。与此同时，他们将支持对WHI CT参与者的更大，动态人群的推断，该研究的少数超额样本来自该人群，其中一人居住在美国环境保护局（EPA）1-10区，并可能受益于基于科学的建立和遵守更严格的国家环境空气质量标准。

DESCRIPTION (provided by applicant): Epidemiologic studies have linked exposure to ambient particulate matter (PM) air pollution with sub-clinical and clinical cardiovascular disease (CVD). Although PM inhalation also has been linked with increases in inflammatory, oxidative, endothelial, metabolic, and coagulation biomarkers in blood, biomarker discovery and understanding of the molecular mechanisms producing such effects in human populations remain incomplete. We and others have consistently found that PM exposure is associated with altered global and gene-specific methylation measured in peripheral leukocyte DNA, an environmentally inducible and dynamic epigenetic mechanism that controls gene expression. DNA methylation in leukocytes and other tissues also has been associated with CVD, implicating it as a primary molecular mechanism mediating the cardiovascular effects of environmental exposures. However, few studies have examined the epigenetics of PM air pollution. Those that have tend to be underpowered, unreplicated, cross-sectional analyses of candidate gene DNA methylation conducted within environmentally homogeneous, single-city populations of white men, without attention to other factors capable of affecting methylation and in turn, CVD risk. We therefore propose to conduct a two- stage, longitudinal study of associations between PM air pollution, DNA methylation, and CVD risk factors among independent subsets of the exam site- and race-stratified, randomly selected 6% minority oversample of approximately 4,300 Women's Health Initiative clinical trial (WHI CT) participants who had fasting blood draws and resting, standard, twelve-lead electrocardiograms (ECGs) repeated at three-year intervals from 1993 to 2004. Stage 1 will focus on the interrogation, discovery and ranking of >450,000 DNA methylation sites potentially sensitive to PM in 1999-2001 blood samples from 800 of the participants. In up to three blood samples collected serially from the remaining 3,500 participants in 1993-2004, Stage 2 will focus on the longitudinal validation of the ten most PM-sensitive DNA methylation sites identified by Stage 1, the temporal relationship between PM and DNA methylation at those sites, and that between site-specific DNA methylation, CVD risk factors, and CVD. The proposed epigenetic data analyses will be conducted within a phenomics framework, well-powered and appropriately adjusted for both ancestral admixture and multiple comparisons. Findings will be externally validated in the ARIC and NAS cohorts. Generalizable findings will advance understanding of epigenetic mechanisms underlying, and biomarkers identifying susceptibility to PM-mediated CVD risk in pre- and post-menopausal women, younger black and older white men. At the same time, they will support inference to the larger, dynamic population of WHI CT participants from which the study's minority oversample was drawn, one living in U.S. Environmental Protection Agency (EPA) Regions 1-10 and potentially benefitted by the science-based establishment of and compliance with stricter National Ambient Air Quality Standards.