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).


METHODS
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.
Osawa
Haruhiko
H
Department of Molecular and Genetic Medicine, Ehime University Graduate School of Medicine, Ehime Japan. harosawa@m.ehime-u.ac.jp
Yamada
Kazuya
K
Tabara
Yasuharu
Y
Ochi
Masaaki
M
Onuma
Hiroshi
H
Nishida
Wataru
W
Shimizu
Ikki
I
Kawamoto
Ryuichi
R
Fujii
Yasuhisa
Y
Miki
Tetsuro
T
Ohashi
Jun
J
Makino
Hideichi
H
D041721:3T3-L1 Cells; D000368:Aged; D000818:Animals; D001665:Binding Sites / Q000235:genetics; D016022:Case-Control Studies; D002478:Cells, Cultured; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000378:metabolism; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D051379:Mice; D008875:Middle Aged; D048055:Mitogen-Activated Protein Kinase 8 / Q000235:genetics* / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D013379:Substrate Specificity; D050656:Transcription Factor AP-2 / Q000378:metabolism*
D050656:Transcription Factor AP-2; D048055:Mitogen-Activated Protein Kinase 8