The Association of Common Polymorphisms in MiR-196a2 with Waist to Hip Ratio and MiR-1908 with Serum Lipid and Glucose

Objective: MicroRNAs (miRNAs) have been implicated in the regulation of cardiometabolic disorders. Given the crucial role of miRNAs in gene expression, genetic variation within miRNA genes is expected to affect miRNA function and substantially contribute to disease risk.

Methods: 2,320 variants in miRNA-encoding sequences were systematically retrieved, and their associations with 17 cardiometabolic traits/diseases were investigated, using genome-wide association studies (GWAS) on glycemic indices, anthropometric measures, lipid traits, blood pressure, coronary artery disease, and type 2 diabetes. Next, target genes of the identified miRNAs that may mediate their effect on the phenotypes were examined. Furthermore, trans- expression quantitative trait loci analysis and luciferase reporter assay to provide functional evidence for our findings were performed.

Results: rs11614913:C/T in miR-196a2 was associated with waist to hip ratio (P-value=1.7 × 10(-5) , β = 0.023). Two target genes, SFMBT1 and HOXC8, which may mediate this association were identfied, and they were shown experimentally as direct targets of miR-196a2. Moreover, rs174561:C/T in miR-1908 was found to be associated with total cholesterol (P-value=6.5 × 10(-16) , β=0.044), LDL-cholesterol (P-value=4.3 × 10(-18) , β=0.049), HDL-cholesterol (P-value=1.7 × 10(-6) , β=0.026), triglyceride (P-value=7.8 × 10(-14) , β=0.038), and fasting glucose (P-value=4.3 × 10(-10) , β=0.02). In addition, a number of miR-1908 target genes were highlighted as potential mediators.

Conclusions: The results indicated miRNA-dependent regulation of fat distribution by miR-196a2 and of lipid metabolism by miR-1908.