From the Departments of aEnvironmental Health and cEpidemiology, Harvard School of Public Health, Boston, MA; bDepartment of Biomedical and Clinical Sciences "Luigi Sacco," University of Milan, Milan, Italy; dLaboratory of Environmental Epigenetics, Department of Environmental and Occupational Health, University of Milan, Milan, Italy; eVA Normative Aging Study, Veterans Affairs Boston Healthcare System and the Department of Medicine, Boston University School of Medicine, Boston, MA; and fGenetic Epidemiology Unit, Channing Laboratory, Brigham and Women's Hospital, Boston, MA.
Epidemiology. 2014 Jan;25(1):68-78. doi: 10.1097/EDE.0000000000000026.
Ambient particulate matter (PM) has been associated with mortality and morbidity for cardiovascular disease. MicroRNAs control gene expression at a posttranscriptional level. Altered microRNA expression has been reported in processes related to cardiovascular disease and PM exposure, such as systemic inflammation, endothelial dysfunction, and atherosclerosis. Polymorphisms in microRNA-related genes could influence response to PM.
We investigated the association of exposure to ambient particles in several time windows (4-hour to 28-day moving averages) and blood leukocyte expression changes in 14 candidate microRNAs in 153 elderly males from the Normative Aging Study (examined 2005-2009). Potential effect modification by six single nucleotide polymorphisms (SNPs) in three microRNA-related genes was investigated. Fine PM (PM2.5), black carbon, organic carbon, and sulfates were measured at a stationary ambient monitoring site. Linear regression models, adjusted for potential confounders, were used to assess effects of particles and SNP-by-pollutant interaction. An in silico pathway analysis was performed on target genes of microRNAs associated with the pollutants.
We found a negative association for pollutants in all moving averages and miR-1, -126, -135a, -146a, -155, -21, -222, and -9. The strongest associations were observed with the 7-day moving averages for PM2.5 and black carbon and with the 48-hour moving averages for organic carbon. The association with sulfates was stable across the moving averages. The in silico pathway analysis identified 18 pathways related to immune response shared by at least two microRNAs; in particular, the "high-mobility group protein B1/advanced glycosylation end product-specific receptor signaling pathway" was shared by miR-126, -146a, -155, -21, and -222. No important associations were observed for miR-125a-5p, -125b, -128, -147, -218, and -96. We found significant SNP-by-pollutant interactions for rs7813, rs910925, and rs1062923 in GEMIN4 and black carbon and PM2.5 for miR-1, -126, -146a, -222, and -9, and for rs1640299 in DGCR8 and SO4 for miR-1 and -135a.
Exposure to ambient particles could cause a downregulation of microRNAs involved in processes related to PM exposure. Polymorphisms in GEMIN4 and DGCR8 could modify these associations.
环境颗粒物（PM）与心血管疾病的死亡率和发病率有关。microRNA 在后转录水平控制基因表达。在与心血管疾病和 PM 暴露相关的过程中，如全身炎症、内皮功能障碍和动脉粥样硬化，已经报道了 microRNA 表达的改变。microRNA 相关基因的多态性可能会影响对 PM 的反应。
我们研究了暴露于环境颗粒的关联在几个时间窗口（4 小时至 28 天的移动平均值）和在 153 名老年男性的血液白细胞中表达的变化在 14 个候选 microRNA 中来自规范老化研究（检查 2005-2009）。研究了三个 microRNA 相关基因中的六个单核苷酸多态性（SNP）的潜在效应修饰。在一个固定的环境监测点测量细颗粒物（PM2.5）、黑碳、有机碳和硫酸盐。使用线性回归模型，调整潜在的混杂因素，评估粒子和 SNP-污染物相互作用的影响。对与污染物相关的 microRNA 的靶基因进行了计算机途径分析。
我们发现所有移动平均值和 miR-1、-126、-135a、-146a、-155、-21、-222 和 -9 的污染物呈负相关。与 PM2.5 和黑碳的 7 天移动平均值以及与有机碳的 48 小时移动平均值观察到最强的关联。硫酸盐的关联在移动平均值之间是稳定的。计算机途径分析确定了 18 个与免疫反应相关的途径，至少有两个 microRNA 与之相关；特别是“高迁移率族蛋白 B1/晚期糖基化终产物特异性受体信号通路”与 miR-126、-146a、-155、-21 和 -222 共享。miR-125a-5p、-125b、-128、-147、-218 和 -96 没有观察到重要的关联。我们发现 GEMIN4 和黑碳以及 miR-1、-126、-146a、-222 和 -9 中 rs7813、rs910925 和 rs1062923 以及 DGCR8 和 SO4 中 rs1640299 与 miR-1 和 -135a 的污染物之间存在显著的 SNP-污染物相互作用。
暴露于环境颗粒可能导致与 PM 暴露相关的过程中涉及的 microRNA 下调。GEMIN4 和 DGCR8 中的多态性可能会改变这些关联。
