Goda Naoki, Murase Haruna, Kasezawa Nobuhiko, Goda Toshinao, Yamakawa-Kobayashi Kimiko
Laboratory of Human Genetics, School of Food and Nutritional Sciences, Graduate School of Integrated Pharmaceutical and Nutritional Sciences, University of Shizuoka, Shizuoka, 422-8526, Japan.
Department of Data Managements for Health Evaluation & Promotion, Shizuoka Medical Center, Shizuoka, 422-8033, Japan.
BMC Med Genet. 2015 Sep 2;16:75. doi: 10.1186/s12881-015-0219-5.
Recent 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.
Genotypes 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.
One 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).
We 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.
近期全基因组关联研究（GWAS）已鉴定出许多与2型糖尿病（T2DM）相关的单核苷酸多态性（SNP）。然而，大多数SNP的功能作用尚未阐明。微小RNA（miRNA）是基因表达的关键调节因子，参与包括T2DM在内的各种疾病的发生和发展。在本研究中，我们调查了常见SNP是否调节miRNA介导的基因表达调控，以及miRNA结合位点中的此类SNP是否与T2DM易感性相关。
在353例T2DM患者和448例对照受试者中测定了7个T2DM易感基因的11个3'非翻译区（UTR）SNP的基因型。此外，使用荧光素酶报告基因检测研究了miRNA与肝细胞核因子1β（HNF1B）基因中3'UTR的相互作用。
HNF1B基因中的一个3'UTR SNP（rs2229295）与T2DM显著相关，与对照组相比，T2DM患者中A等位基因（rs2229295）的频率降低。荧光素酶报告基因检测表明，该SNP（rs2229295）改变了两种miRNA（hsa-miR-214-5p和hsa-miR-550a-5p）的结合。
我们通过体外荧光素酶报告基因检测检测到了hsa-miR-214-5p/hsa-miR-550a-5p与HNF1B基因3'UTR SNP的相互作用，并提出此类miRNA的结合调节HNF1B基因的表达和T2DM的易感性。
