空气细颗粒物致机体表观遗传的变化特征及与心血管损害发生的联系

Accumulating evidence has suggested that exposure to fine particulate matter (PM) is associated with increased risk of early cardiovascular damage and cardiovascular disease, but the epigenetic changes and their association with the occurrence of cardiovascular damage remains unclear so far. We plan to test dynamic changes of DNA methylation levels, plasma LncRNA, MiRNA and inflammatory cytokines and their interactions in 60 volunteers of community residents from the cohort of two cities (Wuhan and Zhuhai) at baseline, first and second follow-up using Illumina HumanMethylation450k Bead Chip, LncRNA and MiRNA array chips. Personal exposures to PM10, PM2.5, polycyclic aromatic hydrocarbons and metals were obtained for 24h, and 24h heart variability rate (HRV) indices and silent myocardial ischemia were measured using 3-channel Holter monitor. 12 urinary PAHs metabolites and 23 urinary metals will be detected. We aim to discover significant changes of DNA methylation, LncRNA, MiRNA and inflammatory cytokines between baseline and twice follow-up, and explore whether there are dose-response relationships between PM2.5, PAHs and metals and DNA methylation, LncRNA, MiRNA and cytokines, and investigate their interaction effect on the changes of HRV and main indexes of cardiovascular characteristics. We will further validate significant changes of DNA methylation, LncRNA, MiRNA and cytokines among 1000 individuals from Wuhan-Zhuhai cohort, and identify the key markers of epigenetic and cytokines involved in early cardiovascular damage. Finally, we will analyze an epigenome-wide association analysis of acute coronary syndrome (ACS) incidence on the 350 pairs nested ACS-control, and examined the causal relations of the identified top hits with the occurrence of ACS. Our results will provide scientific evidences for further elucidation of the mechanisms of cardiovascular damage, and to establish an optimal model for prediction of cardiovascular damage caused by PMs.

空气颗粒物（PM）污染显著增加了心血管早期损伤和心血管疾病的发生，但其所致机体表观遗传的变化特征及与心血管损害发生的联系不清楚。本项目利用已在武汉（高污染）和珠海（低污染）建立的队列中，对在基线和两次随访均具有24h个体PM10、PM2.5和主要成分（多环芳烃、CO、重金属）测定的60个居民，采用芯片动态检测DNA甲基化、血浆LncRNA和miRNAs以及炎性细胞因子的变化与交互作用，分析PMs及主要成分与上述改变的剂量-反应关系，分析其水平与炎性损伤、心率变异性和心肌缺血改变的联系，并在1000人具有内外暴露测定的队列中进行验证，找出PMs及主要成分致机体表观遗传的变化特征及与心血管早期损伤的因果联系。进而在最严重的急性冠脉综合征（ACS）巢氏病例对照中，分析主要成分的内暴露水平与上述改变是否与ACS发生有因果关系，为PMs致心血管损伤发生机制的阐明和构建更加精准的预测模型提供科学依据。

空气细颗粒物（PM2.5）污染显著增加了心血管早期损伤和心血管疾病的发生，但其所致机体表观遗传的变化特征及与心血管损害发生的关联性并不清楚。基于该项目，申请人及其团队结合武汉-珠海精细队列和前瞻性队列，对人群进行多次追踪随访、环境和个体PM2.5内、外暴露测定和心血管损害指标测定。研究成果如下：1、基于前瞻性队列，探讨不同水平室内空气污染的心血管健康危害的关联性，提供了固体燃料使用与全死因死亡、心肺疾病死亡风险升高的重要科学证据，并提出转变为使用燃烧时产生较低水平污染物的清洁燃料，和烹饪时使用通风设施均可降低相关死亡风险；2、探讨空气PM2.5及其金属、多环芳烃组分对机体包括DNA甲基化、miRNA、lncRNA在内的表观遗传改变的影响，发现多环芳烃暴露可加快DNA甲基化年龄的增加；发现并验证了3个与个体PM2.5暴露相关、16个与不同PM2.5金属组分相关的miRNA，和4个与PM2.5暴露相关的lncRNA；3、在PM2.5及其重要组分、表观遗传与早期心血管损伤和急性冠脉综合征（ACS）发生风险的关联性研究方面，发现DNA甲基化可能是PAHs暴露致心率变异性降低的潜在调控机制之一；金属和致癌性多环芳烃联合暴露存在着协同交互作用，可影响miRNA表达水平，并与心率变异性改变等早期心血管损伤程度相关；发现DNA甲基化可通过调节基因的表达参与ACS的发生和发展，继而影响ACS风险和发病。此外，合作研究提示补充B族维生素可防止PM2.5诱导的DNA甲基化异常，B族维生素个体干预将可能成为保护人群少受PM2.5损害的防治手段。这些重要发现揭示了居民室内空气污染致健康危害的严重程度，为阐明空气PM2.5暴露所致心血管损害的发生机制提供了新的表观遗传学依据，也为心血管危险因素的控制、心血管疾病的靶向预防和干预对策提供了新的思路。