ABSTRACT

Air pollution might affect atherosclerosis through DNA methylation changes in cells crucial to atherosclerosis, such as monocytes. We conducted an epigenome-wide study of DNA methylation in CD14+ monocytes and long-term ambient air pollution exposure in adults participating in the Multi-Ethnic Study of Atherosclerosis (MESA). We also assessed the association between differentially methylated signals and cis-gene expression. Using spatiotemporal models, one-year average concentrations of outdoor fine particulate matter (PM_2.5) and oxides of nitrogen (NO_X) were estimated at participants’ homes. We assessed DNA methylation and gene expression using Illumina 450k and HumanHT-12 v4 Expression BeadChips, respectively (n = 1,207). We used bump hunting and site-specific approaches to identify differentially methylated signals (false discovery rate of 0.05) and used linear models to assess associations between differentially methylated signals and cis-gene expression. Four differentially methylated regions (DMRs) located on chromosomes 5, 6, 7, and 16 (within or near SDHAP3, ZFP57, HOXA5, and PRM1, respectively) were associated with PM_2.5. The DMRs on chromosomes 5 and 6 also associated with NO_X. The DMR on chromosome 5 had the smallest p-value for both PM_2.5 (p = 1.4×10⁻⁶) and NO_X (p = 7.7×10⁻⁶). Three differentially methylated CpGs were identified for PM_2.5, and cg05926640 (near TOMM20) had the smallest p-value (p = 5.6×10⁻⁸). NO_X significantly associated with cg11756214 within ZNF347 (p = 5.6×10⁻⁸). Several differentially methylated signals were also associated with cis-gene expression. The DMR located on chromosome 7 was associated with the expression of HOXA5, HOXA9, and HOXA10. The DMRs located on chromosomes 5 and 16 were associated with expression of MRPL36 and DEXI, respectively. The CpG cg05926640 was associated with expression of ARID4B, IRF2BP2, and TOMM20. We identified differential DNA methylation in monocytes associated with long-term air pollution exposure. Methylation signals associated with gene expression might help explain how air pollution contributes to cardiovascular disease.

摘要

空气污染可能通过对动脉粥样硬化至关重要的细胞（例如单核细胞）的 DNA 甲基化变化影响动脉粥样硬化。我们对参与动脉粥样硬化多种族研究 (MESA) 的成年人的 CD14+ 单核细胞 DNA 甲基化和长期环境空气污染暴露进行了全表观基因组研究。我们还评估了差异甲基化信号与顺式基因表达之间的关联。使用时空模型，估算了参与者家中室外细颗粒物 (PM _2.5 ) 和氮氧化物 (NO _X )的一年平均浓度。我们分别使用 Illumina 450k 和 HumanHT-12 v4 Expression BeadChips 评估了 DNA 甲基化和基因表达 (n = 1,207)。我们使用凹凸狩猎和位点特异性方法来识别差异甲基化信号（错误发现率为0.05），并使用线性模型来评估差异甲基化信号和顺式基因表达之间的关联。位于 5、6、7 和 16 号染色体上的四个差异甲基化区域 (DMR)（分别位于SDHAP3、ZFP57、HOXA5和PRM1内或附近）与 PM _2.5相关。5 号和 6 号染色体上的 DMR 也与 NO _X相关。5 号染色体上的 DMR 对于 PM _2.5 (p = 1.4×10 ^-6 ) 和 NO _X (p = 7.7×10 ^-6 ) 具有最小的 p 值。_{PM 2.5}鉴定出三个差异甲基化的CpG ，cg05926640（TOMM20附近）具有最小的p 值（p = 5.6×10 ^-8）。NO _X与ZNF347内的cg11756214 显着相关(p = 5.6×10 ^-8 )。一些差异甲基化信号也与顺式基因表达相关。位于7号染色体上的DMR与HOXA5、HOXA9和HOXA10的表达相关。位于5号和16号染色体上的DMR分别与MRPL36和DEXI的表达相关。CpG cg05926640 与ARID4B、IRF2BP2和TOMM20的表达相关。我们发现单核细胞中的差异 DNA 甲基化与长期空气污染暴露相关。与基因表达相关的甲基化信号可能有助于解释空气污染如何导致心血管疾病。