PMID- 10084598
OWN - NLM
STAT- MEDLINE
DCOM- 19990413
LR  - 20081121
IS  - 0021-972X (Print)
IS  - 0021-972X (Linking)
VI  - 84
IP  - 3
DP  - 1999 Mar
TI  - The hepatic nuclear factor-1alpha G319S variant is associated with early-onset
      type 2 diabetes in Canadian Oji-Cree.
PG  - 1077-82
AB  - 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.
FAU - Hegele, R A
AU  - Hegele RA
AD  - Robarts Research Institute, University of Western Ontario, London, Canada.
      robert.hegele@rri.on.ca
FAU - Cao, H
AU  - Cao H
FAU - Harris, S B
AU  - Harris SB
FAU - Hanley, A J
AU  - Hanley AJ
FAU - Zinman, B
AU  - Zinman B
LA  - eng
GR  - DK44597-01/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - J Clin Endocrinol Metab
JT  - The Journal of clinical endocrinology and metabolism
JID - 0375362
RN  - 0 (DNA-Binding Proteins)
RN  - 0 (HNF1A protein, human)
RN  - 0 (HNF1B protein, human)
RN  - 0 (Hepatocyte Nuclear Factor 1-alpha)
RN  - 0 (Nuclear Proteins)
RN  - 0 (Transcription Factors)
RN  - 126548-29-6 (Hepatocyte Nuclear Factor 1)
RN  - 138674-15-4 (Hepatocyte Nuclear Factor 1-beta)
SB  - IM
MH  - Adolescent
MH  - Adult
MH  - Age of Onset
MH  - Alleles
MH  - Base Sequence/genetics
MH  - Body Mass Index
MH  - Canada
MH  - Child
MH  - *DNA-Binding Proteins
MH  - Diabetes Mellitus, Type 2/blood/*epidemiology/*genetics/pathology
MH  - Female
MH  - Gene Frequency
MH  - Genetic Variation/*physiology
MH  - Genotype
MH  - Hepatocyte Nuclear Factor 1
MH  - Hepatocyte Nuclear Factor 1-alpha
MH  - Hepatocyte Nuclear Factor 1-beta
MH  - Humans
MH  - Indians, North American/*genetics
MH  - Male
MH  - Middle Aged
MH  - *Nuclear Proteins
MH  - Transcription Factors/*genetics
EDAT- 1999/03/20 00:00
MHDA- 1999/03/20 00:01
CRDT- 1999/03/20 00:00
PHST- 1999/03/20 00:00 [pubmed]
PHST- 1999/03/20 00:01 [medline]
PHST- 1999/03/20 00:00 [entrez]
AID - 10.1210/jcem.84.3.5528 [doi]
PST - ppublish
SO  - J Clin Endocrinol Metab. 1999 Mar;84(3):1077-82. doi: 10.1210/jcem.84.3.5528.