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The Journal of Clinical Endocrinology & Metabolism Vol. 84, No. 3 1077-1082
Copyright © 1999 by The Endocrine Society

Original Studies

The Hepatic Nuclear Factor-1{alpha} G319S Variant Is Associated with Early-Onset Type 2 Diabetes in Canadian Oji-Cree1

Robert A. Hegele2, Henian Cao, Stewart B. Harris3, Anthony J. G. Hanley4 and Bernard Zinman

Robarts Research Institute (R.A.H., H.C.) and the Center for Studies in Family Medicine (S.B.H.), University of Western Ontario, London, Canada N6A 5K8; and the Samuel Lunenfeld Research Institute and Department of Medicine, Mount Sinai Hospital, University of Toronto (A.J.G.H., B.Z.), Toronto, Ontario, Canada M5B 1X5

Address all correspondence and requests for reprints to: Dr. Robert A. Hegele, Blackburn Cardiovascular Genetics Laboratory, Robarts Research Institute, 406–100 Perth Drive, London, Ontario, Canada N6A 5K8. E-mail: robert.hegele{at}rri.on.ca

Mutations in the gene encoding hepatic nuclear factor-1{alpha} (HNF-1{alpha}) have been found in patients with maturity-onset diabetes of the young. We identified a new variant in the HNF-1{alpha} 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-1{alpha} 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 postchallenge 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-1{alpha} 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.




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