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Corrado Cilio

Professor

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Common variants in HNF-1 alpha and risk of type 2 diabetes.

Author

  • Johan Holmkvist
  • C Cervin
  • Valeriya Lyssenko
  • W Winckler
  • Dragi Anevski
  • Corrado Cilio
  • Peter Almgren
  • Göran Berglund
  • P Nilsson
  • Tiinamaija Tuomi
  • C Lindgren
  • D Altshuler
  • Leif Groop

Summary, in English

Mutations in the hepatocyte nuclear factor 1-alpha gene (HNF-1 alpha, 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. We studied the effect of four common polymorphisms (rs1920792, I27L, A98V and S487N) in and upstream of the HNF-1 alpha gene on transcriptional activity in vitro, and their possible association with type 2 diabetes and insulin secretion in vivo. Certain combinations of the I27L and A98V polymorphisms in the HNF-1 alpha 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 (=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). This study provides in vitro and in vivo evidence that common variants in the MODY3 gene, HNF-1 alpha, 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.

Department/s

  • Genomics, Diabetes and Endocrinology
  • Mathematical Statistics
  • Diabetes - Immunovirology
  • Internal Medicine - Epidemiology

Publishing year

2006

Language

English

Pages

2882-2891

Publication/Series

Diabetologia

Volume

49

Issue

Oct 11

Document type

Journal article

Publisher

Springer

Topic

  • Endocrinology and Diabetes

Keywords

  • insulin
  • MODY3
  • prospective studies
  • type 2 diabetes
  • mellitus
  • factor 1-alpha
  • case-control studies
  • association study
  • glucose
  • hepatocyte nuclear

Status

Published

Research group

  • Genomics, Diabetes and Endocrinology
  • Diabetes - Immunovirology
  • Internal Medicine - Epidemiology

ISBN/ISSN/Other

  • ISSN: 1432-0428