Department of Environmental Health Sciences, Columbia University Mailman School of Public Health, New York (G.A., A.A.B.).
Population Sciences Branch, National Heart, Lung, and Blood Institute, NIH, Bethesda, MD (M.M.M., D.L., R.J.).
Circulation. 2019 Aug 20;140(8):645-657. doi: 10.1161/CIRCULATIONAHA.118.039357. Epub 2019 Aug 19.
DNA methylation is implicated in coronary heart disease (CHD), but current evidence is based on small, cross-sectional studies. We examined blood DNA methylation in relation to incident CHD across multiple prospective cohorts.
Nine population-based cohorts from the United States and Europe profiled epigenome-wide blood leukocyte DNA methylation using the Illumina Infinium 450k microarray, and prospectively ascertained CHD events including coronary insufficiency/unstable angina, recognized myocardial infarction, coronary revascularization, and coronary death. Cohorts conducted race-specific analyses adjusted for age, sex, smoking, education, body mass index, blood cell type proportions, and technical variables. We conducted fixed-effect meta-analyses across cohorts.
Among 11 461 individuals (mean age 64 years, 67% women, 35% African American) free of CHD at baseline, 1895 developed CHD during a mean follow-up of 11.2 years. Methylation levels at 52 CpG (cytosine-phosphate-guanine) sites were associated with incident CHD or myocardial infarction (false discovery rate<0.05). These CpGs map to genes with key roles in calcium regulation (ATP2B2, CASR, GUCA1B, HPCAL1), and genes identified in genome- and epigenome-wide studies of serum calcium (CASR), serum calcium-related risk of CHD (CASR), coronary artery calcified plaque (PTPRN2), and kidney function (CDH23, HPCAL1), among others. Mendelian randomization analyses supported a causal effect of DNA methylation on incident CHD; these CpGs map to active regulatory regions proximal to long non-coding RNA transcripts.
Methylation of blood-derived DNA is associated with risk of future CHD across diverse populations and may serve as an informative tool for gaining further insight on the development of CHD.
DNA 甲基化与冠心病（CHD）有关，但现有证据基于小型的横断面研究。我们在多个前瞻性队列中研究了血液 DNA 甲基化与 CHD 发病的关系。
来自美国和欧洲的 9 个人群队列使用 Illumina Infinium 450k 微阵列对全基因组血液白细胞 DNA 甲基化进行了分析，并前瞻性地确定了 CHD 事件，包括冠状动脉功能不全/不稳定型心绞痛、确诊性心肌梗死、冠状动脉血运重建和冠状动脉死亡。队列根据年龄、性别、吸烟、教育程度、体重指数、血细胞类型比例和技术变量进行了种族特异性分析。我们在队列间进行了固定效应荟萃分析。
在 11461 名基线时无 CHD 的个体（平均年龄 64 岁，67%为女性，35%为非裔美国人）中，1895 人在平均 11.2 年的随访中发生 CHD。52 个 CpG（胞嘧啶-磷酸-鸟嘌呤）位点的甲基化水平与 CHD 或心肌梗死的发病相关（错误发现率<0.05）。这些 CpG 映射到钙调节相关基因（ATP2B2、CASR、GUCA1B、HPCAL1），以及在全基因组和全基因组外显子组钙血清研究中鉴定出的基因（CASR）、血清钙与 CHD 风险相关的基因（CASR）、冠状动脉钙化斑块（PTPRN2）和肾功能相关基因（CDH23、HPCAL1）等。孟德尔随机化分析支持 DNA 甲基化对 CHD 发病的因果效应；这些 CpG 映射到长非编码 RNA 转录物附近的活性调节区域。
血液源性 DNA 的甲基化与不同人群未来发生 CHD 的风险相关，可能作为一种有用的工具，进一步深入了解 CHD 的发生机制。
