Cao Si, Zeng Youjie, Pang Ke, Chen Minghua, Guo Ren, Wu Nayiyuan, Fang Chao, Deng Huiyin, Zhang Xiaoyi, Xie Xiaohui, Ouyang Wen, Yang Heng
Department of Anesthesiology, Third Xiangya Hospital, Central South University, Changsha, 410013, Hunan, China.
Department of Pharmacy, Third Xiangya Hospital, Central South University, Changsha, 410013, Hunan, China.
Clin Epigenetics. 2025 Jan 2;17(1):1. doi: 10.1186/s13148-024-01808-6.
To explore the mechanisms linking smoking to cardiovascular diseases (CVDs) from an epigenetic perspective.
Mendelian Randomization (MR) analysis was performed to assess the causal effects of smoking behavior and DNA methylation levels at smoking-related CpG sites on nine CVDs, including aortic aneurysm, atrial fibrillation, coronary atherosclerosis, coronary heart disease, heart failure, intracerebral hemorrhage, ischemic stroke, myocardial infarction, subarachnoid hemorrhage. Colocalization analysis was used to further identify key smoking-related CpG sites from the MR causal estimates. Reactome enrichment analysis was used to elucidate the potential mechanisms.
MR analysis indicates that smoking behaviors are significantly associated with an increased risk of nine CVDs (OR > 1, P < 0.05). Through MR and colocalization analysis, five key smoking-related CpG sites were ultimately determined. DNA methylation alteration at cg25313468 (located in the TSS1500 region of REST) is simultaneously associated with the risk of atrial fibrillation, coronary atherosclerosis, coronary heart disease, and myocardial infarction. Additionally, cg21647257 (located in the TSS200 region of CLIP3) is associated with the risk of atrial fibrillation; cg06197751 (located in SGEF gene body) and cg07520810 (located in ARID5B gene body) are associated with the risk of coronary atherosclerosis; cg16822035 (located in MCF2L gene body) is associated with the risk of myocardial infarction. Enrichment analysis suggests that phosphatase and tensin homologue (PTEN) may be involved in the downstream mechanisms of cg25313468 (REST).
This study uncovers the relationship between smoking, DNA methylation, and CVDs, providing new insights into the pathogenic effect of smoking on CVDs from an epigenetic perspective.
从表观遗传学角度探讨吸烟与心血管疾病（CVDs）之间的关联机制。
进行孟德尔随机化（MR）分析，以评估吸烟行为和吸烟相关CpG位点的DNA甲基化水平对九种心血管疾病的因果效应，这些疾病包括主动脉瘤、心房颤动、冠状动脉粥样硬化、冠心病、心力衰竭、脑出血、缺血性中风、心肌梗死、蛛网膜下腔出血。采用共定位分析从MR因果估计中进一步确定关键的吸烟相关CpG位点。利用Reactome富集分析阐明潜在机制。
MR分析表明，吸烟行为与九种心血管疾病风险增加显著相关（OR>1，P<0.05）。通过MR和共定位分析，最终确定了五个关键的吸烟相关CpG位点。cg25313468（位于REST的TSS1500区域）的DNA甲基化改变同时与心房颤动、冠状动脉粥样硬化、冠心病和心肌梗死的风险相关。此外，cg21647257（位于CLIP3的TSS200区域）与心房颤动风险相关；cg06197751（位于SGEF基因体）和cg07520810（位于ARID5B基因体）与冠状动脉粥样硬化风险相关；cg16822035（位于MCF2L基因体）与心肌梗死风险相关。富集分析表明，磷酸酶和张力蛋白同源物（PTEN）可能参与cg25313468（REST）的下游机制。
本研究揭示了吸烟、DNA甲基化与心血管疾病之间的关系，从表观遗传学角度为吸烟对心血管疾病的致病作用提供了新的见解。
