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 AP2alpha.

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 AP2alpha 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 beta cell function index (HOMA-beta) was associated with SNP-1066.

Conclusions: The G/G genotype of MAPK8 SNP-1066 did not affect T2DM susceptibility despite specific binding of AP2alpha.