A Polymorphism in the AMPKα2 Subunit Gene Is Associated With Insulin Resistance and Type 2 Diabetes in the Japanese Population
- Momoko Horikoshi1,
- Kazuo Hara123,
- Jun Ohashi4,
- Kazuaki Miyake5,
- Katsushi Tokunaga4,
- Chikako Ito6,
- Masato Kasuga5,
- Ryozo Nagai2 and
- Takashi Kadowaki137
- 1Department of Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
- 2Department of Clinical Bioinformatics, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
- 3Core Research for Evolution Science and Technology, Japan Science and Technology Corporation, Tokyo, Japan
- 4Department of Human Genetics, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
- 5Department of Clinical Molecular Medicine, Division of Diabetes and Digestive and Kidney Diseases, Graduate School of Medicine, University of Kobe, Kobe, Japan
- 6Hiroshima Atomic Bomb Casualty Council Health Management Center, Hiroshima, Japan
- 7National 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
Abstract
AMP-activated protein kinase (AMPK) acts as a fuel gauge for glucose and lipid metabolism. The gene encoding the α2 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.
- AMPK, AMP-activated protein kinase
- HOMA, homeostasis model assessment
- LD, linkage disequilibrium
- SNP, single nucleotide polymorphism
Footnotes
-
M.H. and K.H. contributed equally to this work.
Additional information for this article can be found in an online appendix available at http://diabetes.diabetesjournals.org.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
-
- Accepted November 14, 2005.
- Received June 7, 2005.
- DIABETES
