心血管健康的DNA甲基化特征为疾病研究提供见解。

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, Peter Durda, 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, 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.

Framingham Heart Study, Framingham, MA.

出版信息

medRxiv. 2024 Nov 20:2024.11.19.24317587. doi: 10.1101/2024.11.19.24317587.

DOI:10.1101/2024.11.19.24317587

PMID:39606375

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11601778/

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 (LE8) score to reflect CVH in five cohorts with diverse ancestry backgrounds. Epigenome-wide association studies (EWAS) for LE8 score were conducted, followed by bioinformatic analyses. DNAm loci significantly associated with LE8 score were used to calculate a CVH DNAm score. We examined the association of the CVH DNAm score with incident CVD, CVD-specific mortality, and all-cause mortality.

RESULTS

We identified 609 CpGs associated with LE8 score at false discovery rate (FDR) < 0.05 in the discovery analysis and at Bonferroni corrected < 0.05 in the multi-cohort replication stage. Most had low-to-moderate heterogeneity (414 CpGs [68.0%] with I < 0.2) in replication analysis. Pathway enrichment analyses and phenome-wide association study (PheWAS) search associated these CpGs with inflammatory or autoimmune phenotypes. We observed enrichment for phenotypes in the EWAS 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 FDR < 0.05. For example, hypomethylation at cg20544516 (; ) associated with lower risk of stroke ( = 8.1e-6). In multivariable prospective analyses, the CVH DNAm score was consistently associated with clinical outcomes across participating cohorts, the reduction in risk of incident CVD, CVD mortality, and all-cause mortality per standard deviation increase in the DNAm score 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 immune response-related pathways may be the key mechanism underpinning the 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八大基本要素（LE8）评分，以反映五个不同祖先背景队列中的CVH。对LE8评分进行全表观基因组关联研究（EWAS），随后进行生物信息学分析。与LE8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）发病、CVD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LE8评分相关的CpG，错误发现率（FDR）<0.05，在多队列复制阶段经Bonferroni校正后<0.05。在复制分析中，大多数具有低至中度异质性（414个CpG [68.0%]，I<0.2）。通路富集分析和全表型组关联研究（PheWAS）搜索将这些CpG与炎症或自身免疫表型相关联。我们在EWAS目录中观察到表型富集，中风富集29倍（P = 2.4e - 15），缺血性心脏病富集21倍（P = 7.4e - 38）。两样本孟德尔随机化（MR）分析显示，在FDR<0.05时，141个CpG与十种表型之间存在显著关联（261个CpG - 表型对）。例如，cg20544516处的低甲基化（P值；效应量）与较低的中风风险相关（P = 8.1e - 6）。在多变量前瞻性分析中，CVH DNAm评分在各参与队列中始终与临床结局相关，DNAm评分每增加一个标准差，CVD发病风险、CVD死亡率和全因死亡率的降低幅度分别为19%至32%、28%至40%和27%至45%。