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AIMS/HYPOTHESIS:Mutations in the hepatocyte nuclear factor 1-alpha gene (HNF-1alpha, 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-1alpha 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-1alpha 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/m(2)) 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-1alpha, 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.

Original publication

DOI

10.1007/s00125-006-0450-x

Type

Journal article

Journal

Diabetologia

Publication Date

12/2006

Volume

49

Pages

2882 - 2891

Addresses

Department of Clinical Sciences, Diabetes and Endocrinology, Clinical Research Center, Malmö University Hospital, Lund University, S-205 02, Malmö, Sweden.

Keywords

Humans, Diabetes Mellitus, Type 2, Body Weight, Insulin, Glucose, Blood Glucose, Arginine, Risk Factors, Case-Control Studies, Amino Acid Substitution, Mutagenesis, Site-Directed, Transcription, Genetic, Polymorphism, Single Nucleotide, Plasmids, Adult, Middle Aged, Female, Male, Overweight, Hepatocyte Nuclear Factor 1-alpha, Genetic Variation, Insulin Secretion