Exploring the Causal Effects of Shear Stress Associated DNA Methylation on Cardiovascular Risk

Abstract

Background and aimsAtherosclerosis 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. Literature search revealed that expression of 11 genes have been found to be associated with differential DNAm due to low shear stress in endothelial cells. We hypothesized a causal relationship between DNAm of shear stress associated genes in human carotid plaque and increased risk of cardiovascular disease. MethodsUsing Mendelian randomisation (MR) analysis, we explored the potential causal role of DNAm of shear stress associated genes on cardiovascular disease risk. We used genetic and DNAm data of 442 carotid endarterectomy derived advanced plaques from the Athero-Express Biobank Study for quantitative trait loci (QTL) discovery and performed MR analysis using these QTLs and GWAS summary statistics of coronary artery disease (CAD) and ischemic stroke (IS). ResultsWe discovered 9 methylation QTLs in plaque for differentially methylated shear stress associated genes. We found no significant effect of shear stress gene promotor methylation and increased risk of CAD and IS. ConclusionsDifferential methylation of shear stress associated genes in advanced atherosclerotic plaques in unlikely to increase cardiovascular risk. Highlights- Plaque-derived DNA methylation in shear stress associated genes shows no significant effect on cardiovascular disease - Genetic variants in shear stress associated genes affect DNA methylation in human carotid plaque - Human validation of atherosclerotic associated genes in murine models