Department of Environmental Health Sciences, Columbia University Mailman School of Public Health, New York, New York.
Department of Chronic Diseases Epidemiology, National Center for Epidemiology, Carlos III Health Institute, Madrid, Spain.
JAMA Cardiol. 2021 Nov 1;6(11):1237-1246. doi: 10.1001/jamacardio.2021.2704.
American Indian communities experience a high burden of coronary heart disease (CHD). Strategies are needed to identify individuals at risk and implement preventive interventions.
To investigate the association of blood DNA methylation (DNAm) with incident CHD using a large number of methylation sites (cytosine-phosphate-guanine [CpG]) in a single model.
DESIGN, SETTING, AND PARTICIPANTS: This prospective study, including a discovery cohort (the Strong Heart Study [SHS]) and 4 additional cohorts (the Women's Health Initiative [WHI], the Framingham Heart Study [FHS], the Atherosclerosis Risk in Communities Study ([ARIC]-Black, and ARIC-White), evaluated 12 American Indian communities in 4 US states; African American women, Hispanic women, and White women throughout the US; White men and White women from Massachusetts; and Black men and women and White men and women from 4 US communities. A total of 2321 men and women (mean [SD] follow-up, 19.1 [9.2] years) were included in the SHS, 1874 women (mean [SD] follow-up, 15.8 [5.9] years) in the WHI, 2128 men and women (mean [SD] follow-up, 7.7 [1.8] years) in the FHS, 2114 men and women (mean [SD] follow-up, 20.9 [7.2] years) in the ARIC-Black, and 931 men and women (mean [SD] follow-up, 20.9 [7.2] years) in the ARIC-White. Data were collected from May 1989 to December 2018 and analyzed from February 2019 to May 2021.
Blood DNA methylation.
Using a high-dimensional time-to-event elastic-net model for the association of 407 224 CpG sites with incident CHD in the SHS (749 events), this study selected the differentially methylated CpG positions (DMPs) selected in the SHS and evaluated them in the WHI (531 events), FHS (143 events), ARIC-Black (350 events), and ARIC-White (121 events) cohorts.
The median (IQR) age of participants in SHS was 55 (49-62) years, and 1359 participants (58.6%) were women. Elastic-net models selected 505 DMPs associated with incident CHD in the SHS beyond established risk factors, center, blood cell counts, and genetic principal components. Among those DMPs, 33 were commonly selected in 3 or 4 of the other cohorts and the pooled hazard ratios from the standard Cox models were significant at P < .05 for 10 of the DMPs. For example, the hazard ratio (95% CI) for CHD comparing the 90th and 10th percentiles of differentially methylated CpGs was 0.86 (0.78-0.95) for cg16604233 (tagged to COL11A2) and 1.23 (1.08-1.39) for cg09926486 (tagged to FRMD5). Some of the DMPs were consistent in the direction of the association; others showed associations in opposite directions across cohorts. Untargeted independent elastic-net models of CHD showed distinct DMPs, genes, and network of genes in the 5 cohorts.
In this multi-cohort study, blood-based DNAm findings supported an association between a complex blood epigenomic signature and CHD that was largely different across populations.
美国印第安人社区冠心病（CHD）负担沉重。需要制定策略来识别高危人群并实施预防干预措施。
使用大量单个模型中的甲基化位点（胞嘧啶-磷酸-鸟嘌呤 [CpG]）来研究血液 DNA 甲基化（DNAm）与 CHD 发病之间的关联。
设计、地点和参与者：这项前瞻性研究包括一个发现队列（强心研究 [SHS]）和另外 4 个队列（妇女健康倡议 [WHI]、弗雷明汉心脏研究 [FHS]、社区动脉粥样硬化风险研究 [ARIC]-黑人和 ARIC-白人），评估了美国 4 个州的 12 个美国印第安人社区；美国各地的非裔美国女性、西班牙裔女性和白人女性；马萨诸塞州的白人男性和女性；以及来自美国 4 个社区的黑人男性和女性以及白人男性和女性。共有 2321 名男性和女性（平均[SD]随访时间，19.1[9.2]年）被纳入 SHS，1874 名女性（平均[SD]随访时间，15.8[5.9]年）被纳入 WHI，2128 名男性和女性（平均[SD]随访时间，7.7[1.8]年）被纳入 FHS，2114 名男性和女性（平均[SD]随访时间，20.9[7.2]年）被纳入 ARIC-黑人，931 名男性和女性（平均[SD]随访时间，20.9[7.2]年）被纳入 ARIC-白人。数据于 1989 年 5 月至 2018 年 12 月收集，并于 2019 年 2 月至 2021 年 5 月进行分析。
血液 DNA 甲基化。
使用高维时间事件弹性网模型对 SHS 中 407224 个 CpG 位点与 CHD 发病的关联进行分析（749 例事件），本研究选择了在 SHS 中差异甲基化 CpG 位置（DMPs）并在 WHI（531 例事件）、FHS（143 例事件）、ARIC-黑人（350 例事件）和 ARIC-白人（121 例事件）队列中进行评估。
SHS 参与者的中位数（IQR）年龄为 55（49-62）岁，其中 1359 名参与者（58.6%）为女性。弹性网模型选择了 505 个 DMPs，这些 DMPs与 SHS 中除已确定的风险因素、中心、血细胞计数和遗传主成分外的 CHD 发病相关。在这些 DMPs 中，有 33 个在其他 3 个或 4 个队列中被共同选择，标准 Cox 模型的汇总风险比在 P<0.05时，有 10 个 DMPs有显著意义。例如，与第 10 百分位相比，第 90 百分位的差异甲基化 CpGs 对 CHD 的风险比（95%CI）为 cg16604233（标记为 COL11A2）的 0.86（0.78-0.95）和 cg09926486（标记为 FRMD5）的 1.23（1.08-1.39）。一些 DMPs 的关联方向一致，而另一些 DMPs 在不同队列中的关联方向相反。在 5 个队列中，针对 CHD 的非靶向独立弹性网模型显示出不同的 DMPs、基因和基因网络。
在这项多队列研究中，基于血液的 DNAm 发现支持了血液表观基因组特征与 CHD 之间的关联，这种关联在不同人群中差异很大。
