Causal Associations of DNA Methylation and Cardiovascular Disease: A Two-Sample Mendelian Randomization Study

Hui Gao; Jiahai Li; Qiaoli Ma; Qinghui Zhang; Man Li; Xiaoliang Hu

doi:10.5334/gh.1324

Causal Associations of DNA Methylation and Cardiovascular Disease: A Two-Sample Mendelian Randomization Study

Glob Heart. 2024 May 14;19(1):48. doi: 10.5334/gh.1324. eCollection 2024.

Authors

Hui Gao^{1

2}, Jiahai Li³, Qiaoli Ma⁴, Qinghui Zhang⁵, Man Li¹, Xiaoliang Hu¹

Affiliations

¹ Department of Cardiovascular Medicine, The First People's Hospital of Shangqiu, Shangqiu 476000, China.
² Graduate School, Dalian Medical University, Dalian, 116044, China.
³ Department of Cardiovascular Medicine, The First People's Hospital of Qinzhou, Qinzhou 535000, China.
⁴ Department of Cardiovascular Medicine, Central Hospital of Zibo, Zibo 255000, China.
⁵ Department of Hypertension, Henan Provincial People's Hospital, Zhengzhou 450000, China.

Abstract

Background: There is growing evidence that concentrations of DNA methylation are associated with cardiovascular disease; however, it is unclear whether this association reflects a causal relationship.

Methods: We utilized a two-sample Mendelian randomization (MR) approach to investigate whether DNA methylation can affect the risk of developing cardiovascular disease in human life. We primarily performed the inverse variance weighted (IVW) method to analyze the causal effect of DNA methylation on multiple cardiovascular diseases. Additionally, to ensure the robustness of our findings, we conducted several sensitivity analyses using alternative methodologies. These analysis methods included maximum likelihood, MR-Egger regression, weighted median method, and weighted model methods.

Results: Inverse variance weighted estimates suggested that an SD increase in DNA methylation Hannum age acceleration exposure increased the risk of cardiac arrhythmias (OR = 1.03, 95% CI 1.00-1.05, p = 0.0290) and atrial fibrillation (OR = 1.03, 95% CI 1.00-1.05, p = 0.0022). We also found that an SD increase in DNA methylation PhenoAge acceleration exposure increased the risk of heart failure (OR = 1.01, 95% CI 1.00-1.03, p = 0.0362). Exposure to DNA methylation-estimated granulocyte proportions was found to increase the risk of hypertension (OR = 1.00, 95% CI 1.00-1.0001, p = 0.0291). Exposure to DNA methylation-estimated plasminogen activator inhibitor-1 levels was found to increase the risk of heart failure (OR = 1.00, 95% CI 1.00-1.00, p = 0.0215).

Conclusion: This study reveals a causal relationship between DNA methylation and CVD. Exposed to high levels of DNA methylation Hannum age acceleration inhabitants with an increased risk of cardiac arrhythmias and atrial fibrillation. DNA methylation PhenoAge acceleration levels exposure levels were positively associated with the increased risk of developing heart failure. This has important implications for the prevention of cardiovascular diseases.

Keywords: Mendelian randomization; cardiovascular disease; methylation.

MeSH terms

Cardiovascular Diseases* / epidemiology
Cardiovascular Diseases* / genetics
DNA Methylation*
Humans
Mendelian Randomization Analysis* / methods
Risk Factors

Grants and funding

This work was supported in part by Henan Province medical science and technology research plan joint construction project: The effect of lipid gene polymorphism on blood lipid level in population of eastern Henan Province (LHGJ20210988).