A Genetic Variant in the Seed Region of miR-4513 Shows Pleiotropic Effects on Lipid and Glucose Homeostasis, Blood Pressure, and Coronary Artery Disease


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Abstract

MicroRNAs (miRNA) play a crucial role in the regulation of diverse biological processes by post-transcriptional modulation of gene expression. Genetic polymorphisms in miRNA-related genes can potentially contribute to a wide range of phenotypes. The effect of such variants on cardiometabolic diseases has not yet been defined. We systematically investigated the association of genetic variants in the seed region of miRNAs with cardiometabolic phenotypes, using the thus far largest genome-wide association studies on 17 cardiometabolic traits/diseases. We found that rs2168518:G>A, a seed region variant of miR-4513, associates with fasting glucose, low-density lipoprotein–cholesterol, total cholesterol, systolic and diastolic blood pressure, and risk of coronary artery disease. We experimentally showed that miR-4513 expression is significantly reduced in the presence of the rs2168518 mutant allele. We sought to identify miR-4513 target genes that may mediate these associations and revealed five genes (PCSK1,BNC2,MTMR3,ANK3, andGOSR2) through which these effects might be taking place. Using luciferase reporter assays, we validatedGOSR2as a target of miR-4513 and further demonstrated that the miRNA-mediated regulation of this gene is changed by rs2168518. Our findings indicate a pleiotropic effect of miR-4513 on cardiometabolic phenotypes and may improve our understanding of the pathophysiology of cardiometabolic diseases.In this study, we found that rs2168518 in the seed region of miR-4513 associates with fasting glucose, LDL-cholesterol and total cholesterol, blood pressure and risk of coronary artery disease. We identified five miR-4513 target genes, GOSR2, ANK3, PCSK1, BNC2, and MTMR3, as potential mediators of these associations. We showed two mechanisms through which the SNP affects miR-4513 function: the mutant allele firstly decreases miR-4513 expression (Fig. 1) and secondly reduces the ability of miR-4513 to repress the target genes expression (Fig. 2).

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