Abstract
Changes in the levels of specific microRNAs (miRNAs) can reduce glucose-stimulated insulin secretion and increase beta-cell apoptosis, two causes of islet dysfunction and progression to type 2 diabetes. Studies have shown that single nucleotide polymorphisms (SNPs) within miRNA genes can affect their expression. We sought to determine whether miRNAs, with a known role in beta-cell function, possess SNPs within the pre-miRNA structure which can affect their expression. Using published literature and dbSNP, we aimed to identify miRNAs with a role in beta-cell function that also possess SNPs within the region encoding its pre-miRNA. Following transfection of plasmids, encoding the pre-miRNA and each allele of the SNP, miRNA expression was measured. Two rare SNPs located within the pre-miRNA structure of two miRNA genes important to beta-cell function (miR-34a and miR-96) were identified. Transfection of INS-1 and MIN6 cells with plasmids encoding pre-miR-34a and the minor allele of rs72631823 resulted in significantly (p < 0.05) higher miR-34a expression, compared to cells transfected with plasmids encoding the corresponding major allele. Similarly, higher levels were also observed upon transfection of HeLa cells. Transfection of MIN6 cells with plasmids encoding pre-miR-96 and each allele of rs41274239 resulted in no significant differences in miR-96 expression. A rare SNP in pre-miR-34a is associated with increased levels of mature miR-34a. Given that small changes in miR-34a levels have been shown to cause increased levels of beta-cell apoptosis this finding may be of interest to studies looking at determining the effect of rare variants on type 2 diabetes susceptibility.
Highlights
Recent genome-wide association studies (GWAS) have identified common (minor allele frequency (MAF) [5 %) single nucleotide polymorphisms (SNPs) associated with risk of type 2 diabetes [1, 2]
Using published literature and dbSNP, we aimed to identify miRNAs with a role in beta-cell function that possess SNPs within the region encoding its pre-miRNA
In dbSNP version 135, we identified three SNPs within the pre-miRNA sequence of miRNAs important to beta-cell function (Table 1)
Summary
Recent genome-wide association studies (GWAS) have identified common (minor allele frequency (MAF) [5 %) single nucleotide polymorphisms (SNPs) associated with risk of type 2 diabetes [1, 2]. Most of these SNPs seem to exert their effect by affecting beta-cell function, rather than insulin action [3]. Recent studies are revealing important roles for specific miRNAs in regulating beta-cell functions, glucose-stimulated insulin secretion and apoptosis (reviewed in [6]). In rodent models, during the progression to diabetes, expression of specific miRNAs has been shown to change, and manipulating the levels of these miRNAs by silencing or mimicry experiments has revealed a causal role in beta-cell dysfunction [7]
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