title: The prevalence of the HNF-1alpha G319S mutation in Canadian aboriginal youth with type 2 diabetes.
abstract: OBJECTIVE
  To investigate the prevalence of the unique HNF-1alpha G319S mutation in a population of aboriginal youth with type 2 diabetes and to describe the relationship between clinical and historical characteristics and the presence or absence of the HNF-1alpha G319S mutation.
  
  
  METHODS
  Participating youth were genotyped for the G319S mutation of the HNF-1alpha gene. Clinical, laboratory, and historical data were collected via chart review (blinded to genotype results). Comparison data were derived from another study involving young nondiabetic pregnant aboriginal women.
  
  
  RESULTS
  A total of 51 youth seen sequentially in a type 2 diabetes clinic participated in this study. Of these, 21 (41.2%) had at least one copy of the mutant allele. The allele frequency in the study population was 0.29 (95% CI 0.20-0.38), which was significantly different from the allele frequency of 0.13 in the comparison population (chi(2) = 6.78, P = 0.009). The frequency of the homozygous mutation (S319/S319) was 0.18. Mean BMI was significantly lower (P = 0.002), mean HbA(1c) was significantly higher (P = 0.02), and acanthosis nigricans was significantly less frequent (P = 0.004) in those with the mutation compared with the wild type. Mean insulin levels were lower and insulin sensitivity (assessed by homeostasis model assessment [HOMA]) was greater in the homozygote group compared with the wild-type group (P = 0.002 and P = 0.0007, respectively). A dose-dependent gradient was observed for these characteristics.
  
  
  CONCLUSIONS
  These data support the association between the HNF-1alpha G319S mutation and early-onset type 2 diabetes in this population. Those with the mutation lacked clinical characteristics of insulin resistance (e.g., obesity and acanthosis nigricans) and had lower insulin levels, suggesting that an insulin-secretory and/or -production defect plays an important role in the development of diabetes in this group. Further investigation of the pathophysiology of the S319 homo- and heterozygote is needed because it may impact treatment and/or prevention of this disease.
authors.affiliation: Department of Pediatrics and Child Health, University of Manitoba, Winnipeg, Canada. esellers@exchange.hsc.mb.ca
authors.forename: Elizabeth A C
authors.initials: EA
authors.lastname: Sellers
authors.forename: Barbara
authors.initials: B
authors.lastname: Triggs-Raine
authors.forename: Cheryl
authors.initials: C
authors.lastname: Rockman-Greenberg
authors.forename: Heather J
authors.initials: HJ
authors.lastname: Dean
mesh_terms: D000293:Adolescent; D000483:Alleles; D044467:American Indian or Alaska Native; D019943:Amino Acid Substitution; D002170:Canada; D002648:Child; D004268:DNA-Binding Proteins / Q000235:genetics; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D051537:Hepatocyte Nuclear Factor 1; D051538:Hepatocyte Nuclear Factor 1-alpha; D051539:Hepatocyte Nuclear Factor 1-beta; D006720:Homozygote; D006801:Humans; D020125:Mutation, Missense; D009687:Nuclear Proteins; D011247:Pregnancy / Q000097:blood*; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D004268:DNA-Binding Proteins; C496487:HNF1A protein, human; C496495:HNF1B protein, human; D051538:Hepatocyte Nuclear Factor 1-alpha; D009687:Nuclear Proteins; D014157:Transcription Factors; D051537:Hepatocyte Nuclear Factor 1; D051539:Hepatocyte Nuclear Factor 1-beta