Coronary artery disease risk factors affected by RNA modification-related genetic variants.

BACKGROUND

Single nucleotide polymorphisms that affect RNA modification (RNAm-SNPs) may have functional roles in coronary artery disease (CAD). The aim of this study was to identify RNAm-SNPs in CAD susceptibility loci and highlight potential risk factors.

METHODS

CAD-associated RNAm-SNPs were identified in the CARDIoGRAMplusC4D and UK Biobank genome-wide association studies. Gene expression and circulating protein levels affected by the RNAm-SNPs were identified by QTL analyses. Cell experiments and Mendelian randomization (MR) methods were applied to test whether the gene expression levels were associated with CAD.

RESULTS

We identified 81 RNAm-SNPs that were associated with CAD or acute myocardial infarction (AMI), including mA-, mA-, mC-, A-to-I- and mG-related SNPs. The mA-SNPs rs3739998 in , rs148172130 in and rs12190287 in and the mG-SNP rs186643756 in were genome-wide significant. The RNAm-SNPs were associated with gene expression (e.g., and ), and the expression levels were associated with CAD. Differential mA methylation and differential expression in FTO-overexpressing human aorta smooth muscle cells and peripheral blood mononuclear cells of CAD patients and controls were detected. The RNAm-SNPs were associated with circulating levels of proteins with specific biological functions, such as blood coagulation, and the proteins (e.g., cardiotrophin-1) were confirmed to be associated with CAD and AMI in MR analyses.

CONCLUSION

The present study identified RNAm-SNPs in CAD susceptibility genes, gene expression and circulating proteins as risk factors for CAD and suggested that RNA modification may play a role in the pathogenesis of CAD.