Exploring the causal inference of shear stress associated DNA methylation in carotid plaque on cardiovascular risk

Abstract

BACKGROUND AND AIMS: Atherosclerosis is a lipid-driven inflammatory disease presumably initiated by endothelial activation. Low vascular shear stress is known for its ability to activate endothelial cells. Differential DNA methylation (DNAm) is a relatively unexplored player in atherosclerotic disease development and endothelial dysfunction. Previous studies showed that the expression of 11 genes was associated with differential DNAm due to low shear stress in murine endothelial cells. We hypothesized a causal relationship between DNAm of shear stress associated genes in human carotid plaque and increased risk of cardiovascular disease. METHODS: Using Mendelian randomisation (MR) analysis, we explored the potential causal role of DNAm of shear stress associated genes on cardiovascular disease risk. We used data from the Athero-Expression Biobank Study for the discovery of methylation quantitative trait loci (mQTLs) in 442 advanced carotid plaques. Next, we performed MR analysis using these mQTLs and publicly available GWAS summary statistics of coronary artery disease (CAD) and ischemic stroke (IS). RESULTS: We discovered 9 mQTLs in plaque in the promoters of shear stress associated genes. We found no significant effect of shear stress gene promoter methylation and increased risk of CAD and IS. CONCLUSIONS: Differential methylation of shear stress associated genes in advanced atherosclerotic plaques in unlikely to increase cardiovascular risk in human.