Importance American Indian communities experience a high burden of coronary heart disease (CHD). Strategies are needed to identify individuals at risk and implement preventive interventions.

Objective 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.

Exposure Blood DNA methylation.

Main Outcome and Measure 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.

Results 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.

Conclusions and Relevance 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.

重要性 美洲印第安人社区的冠心病 (CHD) 负担很重。需要制定策略来识别处于风险中的个人并实施预防性干预措施。

目的 在单一模型中利用大量甲基化位点（胞嘧啶-磷酸-鸟嘌呤[CpG]）研究血液DNA甲基化（DNAm）与冠心病事件的相关性。

设计、设置和参与者 20.9 [7.2] 年）在 ARIC-White。数据收集时间为 1989 年 5 月至 2018 年 12 月，分析时间为 2019 年 2 月至 2021 年 5 月。

暴露 血液 DNA 甲基化。

主要结果和测量 使用高维事件发生时间弹性网络模型将 407 224 个 CpG 位点与 SHS 中的 CHD 事件（749 个事件）联系起来，本研究选择了在SHS 并在 WHI（531 事件）、FHS（143 事件）、ARIC-Black（350 事件）和 ARIC-White（121 事件）队列中评估它们。

结果 SHS 参与者的中位 (IQR) 年龄为 55 (49-62) 岁，1359 名参与者 (58.6%) 为女性。Elastic-net 模型在 SHS 中选择了 505 个与 CHD 事件相关的 DMP，超出了既定的风险因素、中心、血细胞计数和遗传主成分。在这些 DMP 中，通常在 3 或 4 个其他队列中选择 33 个，标准 Cox 模型的汇总风险比在 10 个 DMP 中具有显着性，P  < .05。例如，比较差异甲基化 CpG 的第 90 个和第 10 个百分位数的 CHD 的风险比 (95% CI) 对于 cg16604233（标记为 COL11A2）为 0.86 (0.78-0.95)，对于 cg09926486（标记为FRMD5）为 1.23 (1.08-1.39 )）。一些 DMP 在协会的方向上是一致的；其他人则在不同的队列中显示出相反方向的关联。CHD 的非靶向独立弹性网络模型在 5 个队列中显示出不同的 DMP、基因和基因网络。

结论和相关性 在这项多队列研究中，基于血液的 DNAm 发现支持复杂的血液表观基因组特征与 CHD 之间的关联，这种关联在人群中存在很大差异。