Polymorphism in microRNA-binding site in HNF1B influences the susceptibility of type 2 diabetes mellitus: a population based case-control study.

Naoki Goda,Kimiko Yamakawa-Kobayashi,Haruna Murase,Nobuhiko Kasezawa,Toshinao Goda

doi:10.1186/s12881-015-0219-5

Naoki Goda, Kimiko Yamakawa-Kobayashi + Show 3 more

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https://doi.org/10.1186/s12881-015-0219-5

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Abstract

BackgroundRecent genome-wide association studies (GWAS) have identified many SNPs associated with type 2 diabetes mellitus (T2DM). However, the functional roles for most of the SNPs have not been elucidated. MicroRNAs (miRNAs) are key regulators of gene expression involved in the development and progression of various diseases including T2DM. In this study, we investigated whether commonly occurring SNPs modulate miRNA-directed regulation of gene expression, and whether such SNPs in miRNA-binding sites are associated with the susceptibility for T2DM.MethodsGenotypes of eleven 3′ untranslated region (UTR) SNPs of seven susceptibility genes for T2DM were determined in 353 T2DM patients and 448 control subjects. In addition, the interactions of miRNAs with the 3′UTR in the hepatocyte nuclear factor 1β (HNF1B) gene were investigated using luciferase reporter assays.ResultsOne 3′UTR SNP (rs2229295) in the HNF1B gene was significantly associated with T2DM, and the frequency of an A allele (rs2229295) in T2DM patients was decreased compared with that in controls. Luciferase reporter assays showed that the SNP (rs2229295) altered the binding of two miRNAs (hsa-miR-214-5p and hsa-miR-550a-5p).ConclusionsWe have detected the interactions of hsa-miR-214-5p/hsa-miR-550a-5p and the 3′UTR SNP of the HNF1B gene by in vitro luciferase reporter assays, and propose that the binding of such miRNAs regulates the expression of the HNF1B gene and the susceptibility of T2DM.Electronic supplementary materialThe online version of this article (doi:10.1186/s12881-015-0219-5) contains supplementary material, which is available to authorized users.

Highlights

Recent genome-wide association studies (GWAS) have identified many Single nucleotide polymorphism (SNP) associated with type 2 diabetes mellitus (T2DM)
These data indicate that the A allele of 3′untranslated region (UTR) SNP in the hepatocyte nuclear factor 1B (HNF1B) gene can be a protective allele for T2DM
We have detected the interactions of hsa-miR-214-5p/ hsa-miR-550a-5p and the 3′untranslated regions (3′UTRs) of the HNF1B gene by in vitro luciferase reporter assays, and our results suggest that binding of hsa-miR-214-5p and hsa-miR-550a-5p may regulate the expression of the HNF1B gene

Summary

Introduction

Recent genome-wide association studies (GWAS) have identified many SNPs associated with type 2 diabetes mellitus (T2DM). MicroRNAs (miRNAs) are endogenous noncoding RNAs (19–25 nucleotides in length) that induce the translational repression and degradation of target mRNAs by complementarily binding to their 3′UTR [7]. By silencing their target gene expression, miRNAs are involved in a variety of biological processes, as well as the development and progression of human diseases including cancer and T2DM [8,9,10,11,12,13]. Previous studies showed that SNPs within or proximal to miRNAbinding sites in target genes have the potential to either create or destroy binding sites, which affects the

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