Genetic variation in the hypoxia-inducible factor-1α gene is associated with type 2 diabetes in Japanese

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 beta-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 alpha (HIF-1 alpha) in response to hypoxia. Design and Patients: In this study, we examined all regions of the HIF-1 alpha 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 alpha 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 alpha is associated with the occurrence of type 2 diabetes and suggests that the P582S HIF-1 alpha mutation should be assessed in larger studies as a risk factor for type 2 diabetes.