AUTHOR=Li Ru , Zhang Huan , Tang Fan , Duan Chengcheng , Liu Dan , Wu Naqiong , Zhang Yonghong , Wang Laiyuan , Mo Xingbo 

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

JOURNAL=Frontiers in Cardiovascular Medicine

VOLUME=9

YEAR=2022

URL=https://www.frontiersin.org/journals/cardiovascular-medicine/articles/10.3389/fcvm.2022.985121

DOI=10.3389/fcvm.2022.985121

ISSN=2297-055X

ABSTRACT=<sec><title>Background</title><p>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.</p></sec><sec><title>Methods</title><p>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.</p></sec><sec><title>Results</title><p>We identified 81 RNAm-SNPs that were associated with CAD or acute myocardial infarction (AMI), including m<sup>6</sup>A-, m<sup>1</sup>A-, m<sup>5</sup>C-, A-to-I- and m<sup>7</sup>G-related SNPs. The m<sup>6</sup>A-SNPs rs3739998 in <italic>JCAD</italic>, rs148172130 in <italic>RPL14</italic> and rs12190287 in <italic>TCF21</italic> and the m<sup>7</sup>G-SNP rs186643756 in <italic>PVT1</italic> were genome-wide significant. The RNAm-SNPs were associated with gene expression (e.g., <italic>MRAS, DHX36, TCF21, JCAD</italic> and <italic>SH2B3</italic>), and the expression levels were associated with CAD. Differential m<sup>6</sup>A 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.</p></sec><sec><title>Conclusion</title><p>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.</p></sec>