四分位间距
危险系数
医学
表观遗传学
DNA甲基化
比例危险模型
内科学
队列
肿瘤科
心脏病学
生物
遗传学
置信区间
基因表达
基因
作者
Ernest Diez Benavente,Robin Hartman,Tim R. Sakkers,Marian Wesseling,Yannicke Sloots,Lotte Slenders,Arjan Boltjes,Barend M. Mol,Gert J. de Borst,Dominique P.V. de Kleijn,Koen H M Prange,Menno P.J. de Winther,Johan Kuiper,Mete Civelek,Sander W. van der Laan,Steve Horvath,N. Charlotte Onland‐Moret,Michal Mokrý,Gérard Pasterkamp,Hester M. den Ruijter
标识
DOI:10.1161/atvbaha.123.320692
摘要
Epigenetic age estimators (clocks) are predictive of human mortality risk. However, it is not yet known whether the epigenetic age of atherosclerotic plaques is predictive for the risk of cardiovascular events.Whole-genome DNA methylation of human carotid atherosclerotic plaques (n=485) and of blood (n=93) from the Athero-Express endarterectomy cohort was used to calculate epigenetic age acceleration (EAA). EAA was linked to clinical characteristics, plaque histology, and future cardiovascular events (n=136). We studied whole-genome DNA methylation and bulk and single-cell transcriptomics to uncover molecular mechanisms of plaque EAA. We experimentally confirmed our in silico findings using in vitro experiments in primary human coronary endothelial cells.Male and female patients with severe atherosclerosis had a median chronological age of 69 years. The median epigenetic age was 65 years in females (median EAA, -2.2 [interquartile range, -4.3 to 2.2] years) and 68 years in males (median EAA, -0.3 [interquartile range, -2.9 to 3.8] years). Patients with diabetes and a high body mass index had higher plaque EAA. Increased EAA of plaque predicted future events in a 3-year follow-up in a Cox regression model (univariate hazard ratio, 1.7; P=0.0034) and adjusted multivariate model (hazard ratio, 1.56; P=0.02). Plaque EAA predicted outcome independent of blood EAA (hazard ratio, 1.3; P=0.018) and of plaque hemorrhage (hazard ratio, 1.7; P=0.02). Single-cell RNA sequencing in plaque samples from 46 patients in the same cohort revealed smooth muscle and endothelial cells as important cell types in plaque EAA. Endothelial-to-mesenchymal transition was associated with EAA, which was experimentally confirmed by TGFβ-triggered endothelial-to-mesenchymal transition inducing rapid epigenetic aging in coronary endothelial cells.Plaque EAA is a strong and independent marker of poor outcome in patients with severe atherosclerosis. Plaque EAA was linked to mesenchymal endothelial and smooth muscle cells. Endothelial-to-mesenchymal transition was associated with EAA, which was experimentally validated. Epigenetic aging mechanisms may provide new targets for treatments that reduce atherosclerosis complications.
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