The hepatic nuclear factor-1alpha G319S variant is associated with early-onset type 2 diabetes in Canadian Oji-Cree

J Clin Endocrinol Metab. 1999 Mar;84(3):1077-82. doi: 10.1210/jcem.84.3.5528.


Mutations in the gene encoding hepatic nuclear factor-1alpha (HNF-1alpha) have been found in patients with maturity-onset diabetes of the young. We identified a new variant in the HNF-1alpha gene, namely G319S, in Ontario Oji-Cree with type 2 diabetes. G319S is within the proline II-rich domain of the trans-activation site of HNF-1alpha and alters a glycine residue that is conserved throughout evolution. S319 was absent from 990 alleles taken from subjects representing six other ethnic groups, suggesting that it is private for Oji-Cree. We found that 1) the S319 allele was significantly more prevalent in diabetic than nondiabetic Oji-Cree (0.209 vs. 0.087; P = 0.000001); 2) S319/S319 homozygotes and S319/G319 heterozygotes, respectively, had odds ratios for type 2 diabetes of 4.00 (95% confidence interval, 2.65-6.03) and 1.97 (95% confidence interval, 1.44-2.70) compared with G319/G319 homozygotes; 3) there was a significant difference in the mean age of onset of type 2 diabetes, with G319/G319, S319/G319, and S319/S319 subjects affected in the fifth, fourth, and third decades of life, respectively. In subjects with type 2 diabetes, we also found significantly lower body mass index and significantly higher post-challenge plasma glucose in S319/S319 and S319/G319 compared with G319/G319 subjects. Finally, among nondiabetic subjects, S319/G319 heterozygotes had significantly lower plasma insulin than G319/G319 homozygotes. The presence of the private HNF-1alpha G319S variant in a large number of Oji-Cree with type 2 diabetes and its strong association with type 2 diabetes susceptibility are unique among human populations. Also, G319S is associated with a distinct form of type 2 diabetes, characterized by onset at an earlier age, lower body mass, and a higher postchallenge plasma glucose.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adolescent
  • Adult
  • Age of Onset
  • Alleles
  • Base Sequence / genetics
  • Body Mass Index
  • Canada
  • Child
  • DNA-Binding Proteins*
  • Diabetes Mellitus, Type 2 / blood
  • Diabetes Mellitus, Type 2 / epidemiology*
  • Diabetes Mellitus, Type 2 / genetics*
  • Diabetes Mellitus, Type 2 / pathology
  • Female
  • Gene Frequency
  • Genetic Variation / physiology*
  • Genotype
  • Hepatocyte Nuclear Factor 1
  • Hepatocyte Nuclear Factor 1-alpha
  • Hepatocyte Nuclear Factor 1-beta
  • Humans
  • Indians, North American / genetics*
  • Male
  • Middle Aged
  • Nuclear Proteins*
  • Transcription Factors / genetics*


  • DNA-Binding Proteins
  • HNF1A protein, human
  • HNF1B protein, human
  • Hepatocyte Nuclear Factor 1-alpha
  • Nuclear Proteins
  • Transcription Factors
  • Hepatocyte Nuclear Factor 1
  • Hepatocyte Nuclear Factor 1-beta