Studies on DNA methylation have the potential to discover mechanisms of cardiovascular disease (CVD) risk. However, the role of DNA methylation in CVD etiology remains unclear. We performed an epigenome-wide association study (EWAS) on CVD in a longitudinal sample of Swedish twins (535 individuals). We selected CpGs reaching the Bonferroni-corrected significance level (2 $$\times$$ 10–7) or the top-ranked 20 CpGs with the lowest P values if they did not reach this significance level in EWAS analysis associated with non-stroke CVD, overall stroke, and ischemic stroke, respectively. We further applied a bivariate autoregressive latent trajectory model with structured residuals (ALT-SR) to evaluate the cross-lagged effect between DNA methylation of these CpGs and cardiometabolic traits (blood lipids, blood pressure, and body mass index). Furthermore, mediation analysis was performed to evaluate whether the cross-lagged effects had causal impacts on CVD. In the EWAS models, none of the CpGs we selected reached the Bonferroni-corrected significance level. The ALT-SR model showed that DNA methylation levels were more likely to predict the subsequent level of cardiometabolic traits rather than the other way around (numbers of significant cross-lagged paths of methylation → trait/trait → methylation were 84/4, 45/6, 66/1 for the identified three CpG sets, respectively). Finally, we demonstrated significant indirect effects from DNA methylation on CVD mediated by cardiometabolic traits. We present evidence for a directional association from DNA methylation on cardiometabolic traits and CVD, rather than the opposite, highlighting the role of epigenetics in CVD development.

中文翻译：

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瑞典双胞胎纵向研究中心血管疾病的表观遗传学病因


DNA 甲基化研究有可能发现心血管疾病 (CVD) 风险机制。然而，DNA 甲基化在 CVD 病因学中的作用仍不清楚。我们对瑞典双胞胎（535 人）的纵向样本进行了 CVD 的全表观基因组关联研究 (EWAS)。我们选择达到 Bonferroni 校正显着性水平 (2 $$\times$$ 10–7) 的 CpG，或者如果在与非中风相关的 EWAS 分析中未达到此显着性水平，则选择排名靠前的 20 个具有最低 P 值的 CpG分别为 CVD、整体中风和缺血性中风。我们进一步应用具有结构化残差的双变量自回归潜在轨迹模型 (ALT-SR) 来评估这些 CpG 的 DNA 甲基化与心脏代谢特征（血脂、血压和体重指数）之间的交叉滞后效应。此外，还进行中介分析以评估交叉滞后效应是否对 CVD 具有因果影响。在 EWAS 模型中，我们选择的 CpG 均未达到 Bonferroni 校正的显着性水平。 ALT-SR模型表明，DNA甲基化水平更有可能预测心脏代谢特征的后续水平，而不是相反（甲基化→性状/性状→甲基化的显着交叉滞后路径的数量为84/4，45/ 6、识别的三个 CpG 集分别为 66/1）。最后，我们证明了 DNA 甲基化对心脏代谢特征介导的 CVD 的显着间接影响。我们提供了 DNA 甲基化与心脏代谢特征和 CVD 之间存在定向关联的证据，而不是相反，强调了表观遗传学在 CVD 发展中的作用。