We hypothesized that common variants at the <i>HNF1A</i> locus (rs1169288 [I27L], rs1800574 [A98V]), which are associated with type 2 diabetes susceptibility, may modify age at diabetes diagnosis in individuals with HNF1A-MODY.
The common variants p.I27L (rs1169288), p.A98V (rs1800574) and p.S487N (rs2464196) of the hepatocyte nuclear factor 1-α (HNF1A) gene have been inconsistently associated with impaired glucose tolerance and/or an increased risk of type 2 diabetes mellitus (T2DM).
Significant associations between the heterozygote A98V genotype and clinical parameters of insulin metabolism were reported but no relationship with type 2 diabetes was obtained.
We studied the effect of four common polymorphisms (rs1920792, I27L, A98V and S487N) in and upstream of the HNF-1alpha gene on transcriptional activity in vitro, and their possible association with type 2 diabetes and insulin secretion in vivo.
Polymorphisms of these genes (Ala45Thr [NEUROD1], Ser199Phe [NEUROG3], and Ala98Val [TCF1]) have been postulated to influence the development of type 2 diabetes.
Five single-nucleotide polymorphisms, rs4977574 (CDKN2A/2B), rs12526453 (PHACTR1), rs646776 (CELSR2-PSRC1-SORT1), rs2259816 (HNF1A), and rs11206510 (PCSK9) showed directionally consistent associations with CHD in the 3 studies, with combined odds ratios (ORs) ranging from 1.17 to 1.25 (p = 0.03 to 0.0002).
Progress to date in the molecular genetics of T2DM in youth is limited to one population, the Oji-Cree Native Canadians, where the private variant - G319S - a variant of HNF1A strongly predisposes to diabetes in children as well as in adults.
The risk of Type 2 diabetes was similar (approximately five-fold increased) for subjects with either the presence of the modified metabolic syndrome or the private HNF1A G319S mutation.
A common variant, G319S, private to the Oji-Cree population, predisposes to type 2 diabetes, but the role of common HNF1alpha variation in European populations has not been comprehensively assessed.
The demonstration of a functional consequence for HNF1A G319S provides 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 dilemma.
Among the Oji-Cree of northern Ontario, we previously identified a novel variant in the HNF1A gene, namely G319S, that was strongly associated with type 2 diabetes.
Because HNF-1alpha is involved in the transcription of several apolipoprotein genes, we tested for an association between the private HNF1A G319S variant and plasma lipoproteins in a sample of 55 unrelated Oji-Cree subjects with type 2 diabetes and 175 unrelated Oji-Cree subjects without type 2 diabetes.
Mutation p.T130I was associated with both early-onset and late-onset diabetes and caused downregulated HNF4A expression, whereas HNF1A polymorphisms p.I27L and p.S487N were associated with the age of diagnosis of diabetes.
These findings suggest that the HNF1A p.I27L (rs1169288) variant may be a significant risk factor of T2DM in normal-weight subjects and that earlier inconsistent results may have been due, in part, to subjects' weight status.
In this study, we asked whether the co-occurrence of risk alleles in or near five genes modulating insulin secretion (TCF7L2 rs7903146, IGF2BP2 rs4402960, CDKAL1 rs7754840, HHEX rs1111875, and HNF1A rs1169288) is associated with a higher risk of IGT/T2D in obese children and adolescents.