心血管健康的DNA甲基化特征为疾病研究提供了线索。

DNA Methylation Signatures of Cardiovascular Health Provide Insights Into Diseases.

作者信息

Carbonneau Madeleine, Li Yi, Qu Yishu, Zheng Yinan, Wood Alexis C, Wang Mengyao, Liu Chunyu, Huan Tianxiao, Joehanes Roby, Guo Xiuqing, Yao Jie, Taylor Kent D, Tracy Russell P, Durda Peter, Liu Yongmei, Johnson W Craig, Post Wendy S, Blackwell Tom, Rotter Jerome I, Rich Stephen S, Redline Susan, Fornage Myriam, Wang Jun, Ning Hongyan, Hou Lifang, Lloyd-Jones Donald, Ferrier Kendra, Min Yuan-I, Carson April P, Raffield Laura M, Teumer Alexander, Grabe Hans J, Völzke Henry, Nauck Matthias, Dörr Marcus, Domingo-Relloso Arce, Fretts Amanda, Tellez-Plaza Maria, Cole Shelley A, Navas-Acien Ana, Wang Meng, Murabito Joanne M, Heard-Costa Nancy L, Prescott Brenton, Xanthakis Vanessa, Mozaffarian Dariush, Levy Daniel, Ma Jiantao

机构信息

Population Sciences Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD (M.C., T.H., R.J., D.L.).

Framingham Heart Study, Framingham, MA (M.C., T.H., R.J., J.M.M., N.L.H.-C., V.X., D.L.).

出版信息

Circulation. 2025 Jul 14. doi: 10.1161/CIRCULATIONAHA.124.073181.

DOI:10.1161/CIRCULATIONAHA.124.073181

PMID:40654086

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12262172/

Abstract

BACKGROUND

The association of overall cardiovascular health (CVH) with changes in DNA methylation (DNAm) has not been well characterized.

METHODS

We calculated the American Heart Association's Life's Essential 8 score to reflect CVH in 5 cohorts with diverse backgrounds (mean age 54 years, 55% women, and enrollment year ranging from 1989 to 2012). Epigenome-wide association studies (EWAS) for Life's Essential 8 score were conducted, followed by bioinformatic analyses. DNAm loci significantly associated with Life's Essential 8 score were used to calculate a CVH DNAm score. We examined the association of the CVH DNAm score with incident cardiovascular disease (CVD), cardiovascular disease-specific mortality, and all-cause mortality.

RESULTS

We identified 609 cytosine-phosphate-guanines (CpGs) associated with Life's Essential 8 score at false discovery rate<0.05 in the discovery analysis and at Bonferroni-corrected <0.05 in the multicohort replication stage. Most had low to moderate heterogeneity (414 CpGs [68.0%] with heterogeneity <0.2) in replication analysis. Pathway enrichment analyses and a phenome-wide association study search associated these CpGs with inflammatory or autoimmune phenotypes. We observed enrichment for phenotypes in the Epigenome-Wide Association Study Catalog, with 29-fold enrichment for stroke (=2.4e-15) and 21-fold for ischemic heart disease (=7.4e-38). Two-sample Mendelian randomization (MR) analysis showed significant association between 141 CpGs and ten phenotypes (261 CpG-phenotype pairs) at false discovery rate<0.05. For example, hypomethylation at cg20544516 ( [microRNA 33b] and [sterol regulatory element-binding transcription factor 1]) is associated with a lower risk of stroke (=8.1e-6). In multivariable prospective analyses, the CVH DNAm score was consistently associated with clinical outcomes across participating cohorts. Per SD increase in the CVH DNAm score, the decrease in risk of incident cardiovascular disease, cardiovascular disease mortality, and all-cause mortality ranged from 19% to 32%, 28% to 40%, and 27% to 45%, respectively.

CONCLUSIONS

We identified new DNAm signatures for CVH across diverse cohorts. Our analyses indicate that multiple biological pathways may be relevant to the observed association between CVH and clinical outcomes.

摘要

背景

总体心血管健康（CVH）与DNA甲基化（DNAm）变化之间的关联尚未得到充分表征。

方法

我们计算了美国心脏协会的生命基本8项评分，以反映5个背景各异的队列（平均年龄54岁，55%为女性，入组年份从1989年至2012年）中的CVH。对生命基本8项评分进行全基因组关联研究（EWAS），随后进行生物信息学分析。与生命基本8项评分显著相关的DNAm位点用于计算CVH DNAm评分。我们研究了CVH DNAm评分与心血管疾病（CVD）、心血管疾病特异性死亡率和全因死亡率之间的关联。

结果

在发现分析中，我们确定了609个与生命基本8项评分相关的胞嘧啶-磷酸-鸟嘌呤（CpG）位点，错误发现率<0.05；在多队列复制阶段，经Bonferroni校正后<0.05。在复制分析中，大多数位点具有低至中度的异质性（414个CpG位点[68.0%]，异质性<0.2）。通路富集分析和全表型关联研究搜索将这些CpG位点与炎症或自身免疫表型相关联。我们在全基因组关联研究目录中观察到表型富集，中风的富集倍数为29倍（=2.4e-15），缺血性心脏病的富集倍数为21倍（=7.4e-38）。两样本孟德尔随机化（MR）分析显示，141个CpG位点与10种表型之间存在显著关联（261个CpG-表型对），错误发现率<0.05。例如，cg20544516位点（[微小RNA 33b]和[甾醇调节元件结合转录因子1]）的低甲基化与中风风险降低相关（=8.1e-6）。在多变量前瞻性分析中，CVH DNAm评分在各参与队列中均与临床结局一致相关。CVH DNAm评分每增加1个标准差，心血管疾病、心血管疾病死亡率和全因死亡率的风险降低幅度分别为19%至32%、28%至40%和27%至45%。