Published in:
01-12-2006 | Article
Common variants in HNF-1 α and risk of type 2 diabetes
Authors:
J. Holmkvist, C. Cervin, V. Lyssenko, W. Winckler, D. Anevski, C. Cilio, P. Almgren, G. Berglund, P. Nilsson, T. Tuomi, C. M. Lindgren, D. Altshuler, L. Groop
Published in:
Diabetologia
|
Issue 12/2006
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Abstract
Aims/hypothesis
Mutations in the hepatocyte nuclear factor 1-α gene (HNF-1α, now known as the transcription factor 1 gene [TCF1]) cause the most common monogenic form of diabetes, MODY3, but it is not known if common variants in HNF-1a are associated with decreased transcriptional activity or phenotypes related to type 2 diabetes, or whether they predict future type 2 diabetes.
Subjects and methods
We studied the effect of four common polymorphisms (rs1920792, I27L, A98V and S487N) in and upstream of the HNF-1α gene on transcriptional activity in vitro, and their possible association with type 2 diabetes and insulin secretion in vivo.
Results
Certain combinations of the I27L and A98V polymorphisms in the HNF-1α gene showed decreased transcriptional activity on the target promoters glucose transporter 2 (now known as solute carrier family 2 [facilitated glucose transporter], member 2) and albumin in both HeLa and INS-1 cells. In vivo, these polymorphisms were associated with a modest but significant impairment in insulin secretion in response to oral glucose. Insulin secretion deteriorated over time in individuals carrying the V allele of the A98V polymorphism (n = 2,293; p = 0.003). In a new case–control (n = 1,511 and n = 2,225 respectively) data set, the I27L polymorphism was associated with increased risk of type 2 diabetes, odds ratio (OR) = 1.5 (p = 0.002; multiple logistic regression), particularly in elderly (age > 60 years) and overweight (BMI > 25 kg/m2) patients (OR = 2.3, p = 0.002).
Conclusions/interpretation
This study provides in vitro and in vivo evidence that common variants in the MODY3 gene, HNF-1α, influence transcriptional activity and insulin secretion in vivo. These variants are associated with a modestly increased risk of late-onset type 2 diabetes in subsets of elderly overweight individuals.