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Genetic Variation in the Hypoxia-Inducible Factor-1 Gene Is Associated with Type 2 Diabetes in Japanese

Department of Ophthalmology (N.Y., S.K.), Gunma University Graduate School of Medicine, 371-8511 Gunma, Japan; Laboratory of Medical Genomics, Biosignal Genome Resource Center (Y.H., N.S., J.T.), Institute for Molecular and Cellular Regulation, Gunma University, 371-8512 Gunma, Japan; Core Research for Evolutional Science and Technology (Y.H., K.I., N.S., J.T.), Japan Science and Technology Corporation, 332-0012 Kawaguchi, Japan; Department of Diabetes and Endocrinology (Y.H., J.T.), Gifu University School of Medicine, Gifu 501-1194, Japan; and Department of Internal Medicine (N.O.), Fujita Health University School of Medicine, 470-1192 Aichi, Japan

Address all correspondence and requests for reprints to: Yukio Horikawa, M.D., Ph.D., Department of Diabetes and Endocrinology, Gifu University School of Medicine, 1-1 Yanagido, Gifu-city, Gifu 501-1194, Japan. E-mail: yhorikaw{at}cc.gifu-u.ac.jp.

Context and Objective: Vascular endothelial growth factor plays a critical role both in neovascularization of proliferative diabetic retinopathy and in angiogenesis of islets in the pancreatic developmental stage in determining ß-cell mass and properties. Vascular endothelial growth factor mRNA levels increase as a result of increased transcriptional activation, mediated predominantly by hypoxia-inducible factor-1 (HIF-1) in response to hypoxia.

Design and Patients: In this study, we examined all regions of the HIF-1 to detect single-nucleotide polymorphisms (SNPs), evaluated the pattern of linkage disequilibrium to analyze haplotypes, and performed association studies in Japanese type 2 diabetes patients with or without retinopathy.

Results: A total of 35 SNPs were found in the gene, 27 of which were reported previously and eight of which were novel. Three of the 35 SNPs were located in coding regions, one in exon 2 (S28Y), and the others in exon 12 (P582S, A588T). The P582S HIF-1 mutation was associated with type 2 diabetes (P = 0.0028) by a consistently higher level of transcriptional activity than wild type, especially under hypoxic condition (P = 0.012), but no association with retinopathy was detected.

Conclusion: This is the first report that HIF-1 is associated with the occurrence of type 2 diabetes and suggests that the P582S HIF-1 mutation should be assessed in larger studies as a risk factor for type 2 diabetes.

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