DNA甲基化在长期空气污染暴露与心血管疾病高危人群血脂水平关系中的中介效应
Mediation effect of DNA methylation on relationship between long-term air pollution exposure and blood lipid level in population at high risk for cardiovascular disease
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摘要:
背景 长期的空气污染暴露会影响人类血脂的正常水平，然而这其中确切的分子生物学机制目前尚不清楚。
目的 探讨DNA甲基化在各项空气污染物（PM2.5、PM10、NO2、SO2、CO和O3）平均暴露1年与心血管疾病高危人群的血脂水平关系中是否具有中介效应。
方法 本研究样本来源于冠心病医疗结果评价和临床转化研究-百万人群项目，共选择了176例研究对象样本，这些研究对象来自中国大陆15个省的61个城市。首先对样本人群血样中的总胆固醇（TC）、甘油三酯（TG）、高密度脂蛋白胆固醇（HDL-C）和低密度脂蛋白胆固醇（LDL-C）等各项血脂指标以及其他生化指标进行检测，同时利用各项污染物1年平均暴露水平的数据以及前期研究已获得的全基因组甲基化芯片（EPIC 850K）数据，通过因果推理检验（CIT）方法识别在空气污染物暴露与血脂水平之间具有中介效应的甲基化位点。
结果 在调整年龄、性别、体重指数（BMI）、目前吸烟情况、饮酒情况、高血压和糖尿病因素后，仅NO2污染物暴露（以每增加10 μg·m-3为1个单位）与TC、LDL-C、非高密度脂蛋白胆固醇（nHDL-C）的水平升高具有相关性估计值（
b ）=0.259，标准误（S b ）=0.084，P =0.002；b =0.173，S b =0.059，P =0.004；b =0.227，S b =0.082，P =0.006），其他空气污染物（SO2、PM10、PM2.5、O3、CO）与血脂水平都不具有相关性（P >0.05）。CIT分析结果显示，在NO2暴露相关的5 615个甲基化位点（P < 0.01）中，分别有2个甲基化位点（无注释基因）、16个甲基化位点（11个有注释基因）和32个（23个有注释基因）甲基化位点介导了NO2暴露增加与TC、LDL-C及nHDL-C水平升高的相关性（P 1 < 0.05，P 2 < 0.05，P 3 < 0.05，P 4>0.05）。结论 NO2长期暴露引起的特定位点DNA甲基化可能与TC、LDL-C和nHDL-C水平升高有相关性。
Abstract:Background Long-term exposure to air pollution affects blood lipids, but the exact molecular biological mechanism is not yet clear.
Objective This study explores a potential mediation effect of DNA methylation on the relationship between one-year average exposure to air pollutants (PM2.5, PM10, NO2, SO2, CO, and O3) and blood lipid levels in population at high risk for cardiovascular disease.
Methods A total of 176 cases were selected from the China Patient-Centered Evaluative Assessment of Cardiac Events Million Persons Project across 61 cities in 15 provinces of China's mainland. The blood levels of total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and other biochemical indicators were measured. Meanwhile, based on the data of one-year average exposure to air pollutants and of genome-wide methylation chips (EPIC 850 k) obtained from previous projects, causal inference test (CIT) method was employed to identify DNA methylation sites that exhibit a mediation effect on the relationship between air pollutant exposure and lipid levels.
Results Only NO2 exposure (per 10 μg·m-3 increase) was associated with elevated levels of TC (
b =0.259,S b =0.084,P =0.002), LDL-C (b =0.173,S b =0.059,P =0.004), and non-HDL-C (nHDL-C) (b =0.227,S b =0.082,P =0.006) after adjustment for age, gender, body mass index (BMI), current smoking, drinking, hypertension, and diabetes, while other air pollutants (SO2, PM10, PM2.5, O3, and CO) were not (P >0.05). The CIT analysis results showed that there were 2 methylation sites (without annotation genes), 16 methylation sites (11 sites with annotation genes), and 32 methylation sites (23 sites with annotation genes) mediating the association between increased NO2 pollutant exposure and elevated levels of TC, LDL-C, and nHDL-C (P 1 < 0.05,P 2 < 0.05,P 3 < 0.05,P 4>0.05) among the included 5 615 methylation loci related with NO2 exposure (P < 0.01), respectively.Conclusion DNA methylation at specific sites caused by long-term NO2 exposure is correlated with elevated levels of TC, LDL-C, and nHDL-C.
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