Hegele et al. (1999) identified a gly319-to-ser (G319S) variant in the HNF1A gene in Ontario Oji-Cree with early-onset type 2 diabetes (125853). G319S is in the proline II-rich domain of the trans-activation site of HNF1A and alters a glycine residue that is conserved throughout evolution. S319 was absent from 990 alleles from 6 other ethnic groups, suggesting that it is private for Oji-Cree. The S319 allele was more prevalent in diabetic than in nondiabetic Oji-Cree (0.209 vs 0.087; P = 0.000001). S319/S319 homozygotes and S319/G319 heterozygotes, respectively, had odds ratios for type 2 diabetes of 4.00 (95% CI, 2.65-6.03) and 1.97 (95% CI, 1.44-2.70) compared with G319/G319 homozygotes. There was a significant difference in the mean age of onset of type 2 diabetes, with G319/G319, S319/G319, and S319/S319 subjects being affected in the fifth, fourth, and third decades of life, respectively. Among nondiabetic subjects, S319/G319 heterozygotes had significantly lower plasma insulin than G319/G319 homozygotes. The authors concluded that the G319S variant 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.
That the majority of Oji-Cree subjects with diabetes did not have the HNF1A S319 variant suggested to Hegele et al. (2000) that there might be other genetic determinants of diabetes susceptibility. In the course of sequencing candidate genes in diabetic subjects who were homozygous for HNF1A G319/G319, they found that some subjects had the PPARG A12 variant (601487.0002). PPARG A12 was strongly associated with type 2 diabetes in women, but not in men. The authors concluded that, when taken together with the previously reported association of diabetes with HNF1A in both men and women, the gender-specific association with PPARG A12 confirms that type 2 diabetes is etiologically complex in the Oji-Cree and that at least 2 genes are involved in determining susceptibility to the disease in this population.
Triggs-Raine et al. (2002) stated that Oji-Cree type 2 diabetes does not resemble MODY, because affected Oji-Cree subjects are obese and insulin-resistant with elevated plasma insulin concentrations, which clearly were insufficient to prevent diabetes onset. They evaluated the in vitro function of HNF1A G319S both to confirm that the mutation had a functional effect and to determine whether this effect was distinct from those of the complete loss-of-function or dominant-negative mutations seen in the MODY3 phenotype. They also evaluated the impact of the HNF1A G319S mutation on the dynamics of type 2 diabetes onset in the whole Sandy Lake Oji-Cree community. They found that the G319S mutation reduced the in vitro ability of HNF1-alpha to activate transcription by approximately 50%, with no effect on DNA binding or protein stability. There was no evidence of a dominant-negative effect of the mutant protein. Disease onset showed significant differences according to G319S genotype when gauged by the age at which half the subjects had become diabetic. Each dose of G319S accelerated median disease onset by approximately 7 years. Thus, the transactivation-deficient HNF1A G319S mutation affects the dynamics of disease onset. The demonstration of a functional consequence for the G319S mutation provided a mechanistic basis for its strong association with Oji-Cree type 2 diabetes and its unparalleled specificity for diabetes prediction in these people, in whom diabetes presents a significant public health problem. The finding also showed that HNF1A mutations can be associated with typical adult-onset insulin-resistant obesity-related diabetes in addition to maturity-onset diabetes of the young. Triggs-Raine et al. (2002) stated that in the Oji-Cree, HNF1A G319S behaves as a susceptibility allele for type 2 diabetes. Among nondiabetic Oji-Cree, fasting plasma insulin concentration was reduced significantly in HNF1A G319S carriers, suggesting that the partial impairment of function is tolerated when there is no insulin resistance. However, among Oji-Cree with type 2 diabetes, both carriers and noncarriers of the mutation had elevated plasma insulin concentration compared with nondiabetic Oji-Cree. The stress of obesity-induced insulin resistance seemed to expose the partial defect in HNF1A G319S carriers, causing expression of the disease.
