The G/G genotype of a single nucleotide polymorphism at –1066 of c-Jun N-terminal kinase 1 gene (MAPK8) does not affect type 2 diabetes susceptibility despite the specific binding of AP2α

Authors


Dr H. Osawa, Department of Molecular and Genetic Medicine, Ehime University Graduate School of Medicine, Toon, Ehime 791–0295, Japan. Tel.: +81 89 960 5647; Fax: +81 89 960 5627; E-mail: harosawa@m.ehime-u.ac.jp

Summary

Objective  The c-Jun N-terminal kinase 1 (JNK1, mitogen-activated kinase 8; MAPK8) phosphorylates insulin receptor substrate-1 (IRS-1) at serine 307, which induces insulin resistance. MAPK8 activity is increased in obese insulin-resistant mice, whereas mapk8 (–/–) mice show decreased adiposity and improved insulin sensitivity. The aim of this study was to determine the relationship between single nucleotide polymorphisms (SNPs) of MAPK8 and type 2 diabetes (T2DM).

Design, patients and measurements  Approximately 2 kb of 5′ flanking and the coding regions were initially sequenced in 24 Japanese T2DM subjects. Identified SNPs were genotyped in 204 T2DM cases and 201 nondiabetic controls. The function of promoter SNP–1066 (g.–1066G > A, rs10857561) was analysed by electrophoretic mobility shift assay (EMSA) and luciferase assay. SNP–1066 was further genotyped in a total of 498 cases and 407 controls, and in 2075 subjects in the general population.

Results  In 204 cases and 201 controls, 11 identified SNPs were not associated with T2DM. These SNPs were in the same linkage disequilibrium (LD) block. The tag SNP–1066 was not associated with T2DM in a total of 498 cases and 407 controls with the power > 80% when the relative risk is > 1·31. Functionally, transcription factor AP2α specifically recognized G but not A at –1066. MAPK8 promoter activity was unchanged between G and A. In 2075 subjects, neither body mass index (BMI), fasting plasma glucose (FPG), homeostasis model assessment insulin resistance index (HOMA-IR), nor β cell function index (HOMA-β) was associated with SNP–1066.

Conclusions  The G/G genotype of MAPK8 SNP–1066 did not affect T2DM susceptibility despite specific binding of AP2α.

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