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DOI: 10.2337/diabetes.55.04.06.db05-0727
© 2006 by the American Diabetes Association
Brief Genetics Reports |
A Polymorphism in the AMPK
2 Subunit Gene Is Associated With Insulin Resistance and Type 2 Diabetes in the Japanese Population
1 Department of Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
2 Department of Clinical Bioinformatics, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
3 Core Research for Evolution Science and Technology, Japan Science and Technology Corporation, Tokyo, Japan
4 Department of Human Genetics, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
5 Department of Clinical Molecular Medicine, Division of Diabetes and Digestive and Kidney Diseases, Graduate School of Medicine, University of Kobe, Kobe, Japan
6 Hiroshima Atomic Bomb Casualty Council Health Management Center, Hiroshima, Japan
7 National Institute of Health and Nutrition, Tokyo, Japan
Address correspondence and reprint requests to Takashi Kadowaki, Department of Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-8655, Japan. E-mail: kadowaki-3im{at}h.u-tokyo.ac.jp
Abbreviations:
AMPK, AMP-activated protein kinase; HOMA, homeostasis model assessment; LD, linkage disequilibrium; SNP, single nucleotide polymorphism
AMP-activated protein kinase (AMPK) acts as a fuel gauge for glucose and lipid metabolism. The gene encoding the 
2 isoform of the catalytic subunit of AMPK (PRKAA2) is located at one of the Japanese type 2 diabetes loci mapped by our previous genome scan (1p36-32). PRKAA2 is, therefore, a good candidate gene for insulin resistance and type 2 diabetes. We screened all nine exons, their exon-intron boundaries, and the 5' and 3' flanking regions of PRKAA2 to identify single nucleotide polymorphisms (SNPs), and we genotyped 192 type 2 diabetic patients and 272 nondiabetic subjects to assess possible associations between genotypes or haplotypes and type 2 diabetes. None of the 10 SNPs genotyped was associated with type 2 diabetes, but the haplotype analysis, consisting of six representative SNPs, revealed one haplotype, with the A (minor) allele for rs2051040 and a major allele for the other five SNPs, to be associated with type 2 diabetes (P = 0.009). This finding was confirmed in two larger replication samples (657 case and 360 control subjects, P = 0.021; and 356 case and 192 control subjects from the same area in Japan, P = 0.007) and a significant P value was obtained in the joint haplotype analysis of all samples (1,205 case and 824 control subjects, P = 0.0001). Furthermore, insulin resistance was associated with rs2051040 in nondiabetic subjects, and those with the A (minor) allele had a higher homeostasis model assessment of insulin resistance index than those who did not (initial control subjects [n = 272], P = 0.002; and joint replication control subjects [n = 552], P = 0.037). We speculate that the PRKAA2 gene influences insulin resistance and susceptibility to type 2 diabetes in the Japanese population.
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