Epigenetic Mechanisms of PM-Mediated CVD Risk

描述(申请人提供)：流行病学研究已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)。尽管吸入PM也与血液中炎症、氧化、内皮、代谢和凝血生物标记物的增加有关，但生物标记物的发现和对在人类群体中产生这些影响的分子机制的了解仍然不完整。我们和其他人一直发现，PM暴露与外周血白细胞DNA中测量的全球和基因特异性甲基化改变有关，这是一种环境可诱导的动态表观遗传机制，控制基因表达。白细胞和其他组织中的DNA甲基化也与心血管疾病有关，这意味着它是介导环境暴露对心血管影响的主要分子机制。然而，很少有研究研究PM空气污染的表观遗传学。对候选基因DNA甲基化的分析往往动力不足、不可复制、横断面分析是在环境同质的单城市白人男性人群中进行的，而没有注意到其他能够影响甲基化并进而导致心血管疾病风险的因素。因此，我们建议对PM空气污染、DNA甲基化和心血管疾病危险因素之间的关系进行两个阶段的纵向研究，在考试地点的独立亚组中，并按种族分层，随机选择6%的少数民族超标样本，约4,300名妇女健康倡议临床试验(WHI CT)参与者在1993至2004年间每三年重复一次空腹抽血和静息标准十二导联心电图(ECG)。第一阶段将集中于对1999-2001年800名参与者的血液样本中可能对PM敏感的&gt；450,000个DNA甲基化位点进行询问、发现和排序。在1993-2004年从其余3500名参与者身上连续采集的多达三个血液样本中，第二阶段将集中于对第一阶段确定的10个PM最敏感的DNA甲基化位点的纵向验证，PM和这些地点DNA甲基化之间的时间关系，以及特定部位DNA甲基化、心血管疾病风险因素和心血管疾病之间的关系。拟议的表观遗传学数据分析将在一个表观组学框架内进行，该框架具有良好的动力，并针对祖先混合和多重比较进行适当调整。研究结果将在ARIC和NAS队列中进行外部验证。概括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、年轻黑人和老年白人男性对PM介导的心血管疾病风险的易感性的生物标记物。同时，他们将支持对WHI CT参与者中更大、更具活力的人群的推断，这项研究的少数过抽样来自其中一个人，其中一个人生活在美国环境保护局(EPA)1-10区，并可能受益于以科学为基础建立并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.