title: Genetic variation in the hypoxia-inducible factor-1alpha gene is associated with type 2 diabetes in Japanese.
abstract: 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-1alpha) in response to hypoxia.
  
  
  METHODS
  In this study, we examined all regions of the HIF-1alpha 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-1alpha 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.
  
  
  CONCLUSIONS
  This is the first report that HIF-1alpha is associated with the occurrence of type 2 diabetes and suggests that the P582S HIF-1alpha mutation should be assessed in larger studies as a risk factor for type 2 diabetes.
authors.affiliation: Department of Ophthalmology, Gunma University Graduate School of Medicine, Japan.
authors.forename: Norihiro
authors.initials: N
authors.lastname: Yamada
authors.forename: Yukio
authors.initials: Y
authors.lastname: Horikawa
authors.forename: Naohisa
authors.initials: N
authors.lastname: Oda
authors.forename: Katsumi
authors.initials: K
authors.lastname: Iizuka
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Shihara
authors.forename: Shoji
authors.initials: S
authors.lastname: Kishi
authors.forename: Jun
authors.initials: J
authors.lastname: Takeda
mesh_terms: D000483:Alleles; D003001:Cloning, Molecular; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000235:genetics*; D003924:Diabetes Mellitus, Type 2 / Q000453:epidemiology* / Q000235:genetics*; D003930:Diabetic Retinopathy / Q000453:epidemiology / Q000235:genetics; D005091:Exons / Q000235:genetics; D005260:Female; D005787:Gene Frequency; D014644:Genetic Variation / Q000502:physiology*; D006239:Haplotypes; D006801:Humans; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007564:Japan / Q000453:epidemiology; D015810:Linkage Disequilibrium / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009687:Nuclear Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D004268:DNA-Binding Proteins; C497442:HIF1A protein, human; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009687:Nuclear Proteins; D014157:Transcription Factors