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


METHODS
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.


RESULTS
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).


CONCLUSIONS
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.
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. s12509@u-shizuoka-ken.ac.jp.
Naoki
N
Goda
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. f11123@u-shizuoka-ken.ac.jp.
Haruna
H
Murase
Department of Data Managements for Health Evaluation & Promotion, Shizuoka Medical Center, Shizuoka, 422-8033, Japan. kasezawa@iki-iki-hp.com.|Present address: Fuji iki-iki Hospital, Health Promotion Center, Temma, Fuji-shi, Shizuoka, 419-0205, Japan. kasezawa@iki-iki-hp.com.
Nobuhiko
N
Kasezawa
Laboratory of Nutritional Physiology, School of Food and Nutritional Sciences, Graduate School of Integrated Pharmaceutical and Nutritional Sciences, University of Shizuoka, Shizuoka, 422-8526, Japan. gouda@u-shizuoka-ken.ac.jp.
Toshinao
T
Goda
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. kobayasi@u-shizuoka-ken.ac.jp.
Kimiko
K
Yamakawa-Kobayashi
D016022:Case-Control Studies; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005838:Genotype; D051539:Hepatocyte Nuclear Factor 1-beta / Q000235:genetics*; D006801:Humans; D007564:Japan; D008156:Luciferases; D008297:Male; D020641:Polymorphism, Single Nucleotide / Q000235:genetics
C496495:HNF1B protein, human; D051539:Hepatocyte Nuclear Factor 1-beta; D008156:Luciferases