Single-nucleotide polymorphisms inside microRNA target sites influence the susceptibility to type 2 diabetes

MicroRNAs (miRNAs) negatively regulate target gene expression by binding to 3'-untranslated region of target mRNA. Single-nucleotide polymorphisms (SNPs) that reside in the miRNA target sites can affect the bindings of miRNAs to mRNAs. Compelling evidence has shown that miRNAs contribute to the etiology of type 2 diabetes (T2DM). We hypothesized that SNPs in diabetes-related miRNA target-binding sites could be associated with the risk of T2DM. We selected 10 SNPs on miRNA-binding sites by using bioinformatics software. Genotypes of T2DM patients (n=1017) and normal controls (n=1059) were analyzed by TaqMan assay. The variant genotypes rs1366600CC and TC/CC in the insulin receptor (INSR) gene, rs2292899GA in the acyl-CoA synthetase 1 (ACSL1) gene and rs11724758AA in the fatty-acid-binding protein 2 (FABP2) gene were associated with T2DM (adjusted odds ratios (ORs) (95% confidence intervals)=2.03 (1.02-4.01), 1.28 (1.04-1.57), 1.22 (1.004-1.49) and 0.76 (0.58-0.997), respectively). The analysis stratified by age, gender, waist circumstance and living habits also revealed these genotypes' effect. Furthermore, crossover analysis indicated those who exposed to both environmental factor and putative risk genotypes did have the highest risk of T2DM. A cumulative effect of SNPs rs1366600, rs2292899 and rs11724758 was observed with individuals carrying 2, 3 and 4-6 risk alleles having a gradually increased risk of T2DM (OR=1.52, 1.81 and 2.28, P for trend <0.001). Our result suggested that INSR rs1366600, ACSL1 rs2292899 and FABP2 rs11724758 could influence the susceptibility to T2DM in Chinese Han population, most likely through their effects on the specific miRNA-binding sites and functional characterizations of three genes are needed.