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. 2025 Jan 2;17(1):1.
doi: 10.1186/s13148-024-01808-6.

Unraveling the causal impact of smoking and its DNA methylation signatures on cardiovascular disease: Mendelian randomization and colocalization analysis

Si Cao #  1 , Youjie Zeng #  1 , Ke Pang  1 , Minghua Chen  1 , Ren Guo  2 , Nayiyuan Wu  3 , Chao Fang  3 , Huiyin Deng  1 , Xiaoyi Zhang  4 , Xiaohui Xie  5 , Wen Ouyang  1 , Heng Yang  6
Affiliations

Unraveling the causal impact of smoking and its DNA methylation signatures on cardiovascular disease: Mendelian randomization and colocalization analysis

Si Cao et al. Clin Epigenetics. .

Abstract

Background: To explore the mechanisms linking smoking to cardiovascular diseases (CVDs) from an epigenetic perspective.

Methods: 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.

Results: 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).

Conclusion: 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.

Keywords: Cardiovascular diseases; Causal inference; Cigarette smoking; DNA methylation; Mendelian randomization; Risk factors.

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Conflict of interest statement

Declarations. Ethics approval and consent to participate: This study was a secondary analysis based on de-identified public datasets; therefore, no additional ethics approval and consent to participate were required. Consent for publication: Not applicable. Competing interests: The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
General flow of this MR study
Fig. 2
Fig. 2
Causal effects of three smoking traits on nine CVDs [A aortic aneurysm; B atrial fibrillation; C coronary atherosclerosis; D coronary heart disease; E heart failure; F intracerebral hemorrhage; G ischemic stroke; H myocardial infarction; I subarachnoid hemorrhage] assessed by the IVW MR approach and meta-analysis
Fig. 3
Fig. 3
Manhattan plots displaying preliminary identification of smoking-related CpG sites significantly associated with A aortic aneurysm, B atrial fibrillation, C coronary atherosclerosis, D coronary heart disease, E heart failure, F intracerebral hemorrhage, G ischemic stroke, H myocardial infarction, and I subarachnoid hemorrhage by MR analysis
Fig. 4
Fig. 4
Regional plot of colocalization evidence between cg25313468 methylation and A atrial fibrillation, B coronary atherosclerosis, C coronary heart disease, and D myocardial infarction
Fig. 5
Fig. 5
Regional plot of colocalization evidence for cg21647257, cg06197751, cg07520810, and cg16822035. A Colocalization between cg21647257 and atrial fibrillation. B Colocalization between cg06197751 and coronary atherosclerosis. C Colocalization between cg07520810 and coronary atherosclerosis. D Colocalization between cg16822035 and myocardial infarction
Fig. 6
Fig. 6
Identification of potential mechanisms of REST gene in four CVDs. A The PPI network of top 500 interacting genes of REST gene generated by STRING database. B Venn diagram identifying intersecting genes between PPI top 500 genes and four CVDs-related genes from DisGeNET database. C Reactome enrichment analysis of atrial fibrillation-related intersecting genes. D Reactome enrichment analysis of coronary atherosclerosis-related intersecting genes. E Reactome enrichment analysis of coronary heart disease-related intersecting genes. F Reactome enrichment analysis of myocardial infarction-related intersecting genes
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