Skip to main content

Lund University Publications

LUND UNIVERSITY LIBRARIES

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

Holmkvist, Johan LU ; Cervin, C ; Lyssenko, Valeriya LU ; Winckler, W ; Anevski, Dragi LU ; Cilio, Corrado LU ; Almgren, Peter LU ; Berglund, Göran LU ; Nilsson, P and Tuomi, Tiinamaija LU orcid , et al. (2006) In Diabetologia 49(Oct 11). p.2882-2891
Abstract
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... (More)
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. (Less)
Please use this url to cite or link to this publication:
author
; ; ; ; ; ; ; ; and , et al. (More)
; ; ; ; ; ; ; ; ; ; ; and (Less)
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
insulin, MODY3, prospective studies, type 2 diabetes, mellitus, factor 1-alpha, case-control studies, association study, glucose, hepatocyte nuclear
in
Diabetologia
volume
49
issue
Oct 11
pages
2882 - 2891
publisher
Springer
external identifiers
  • wos:000241948200011
  • scopus:33750954749
ISSN
1432-0428
DOI
10.1007/s00125-006-0450-x
language
English
LU publication?
yes
id
f28d0da0-3df8-467d-870e-b826d36a4d78 (old id 162369)
alternative location
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=17033837&dopt=Abstract
date added to LUP
2016-04-01 12:16:11
date last changed
2024-01-08 14:28:17
@article{f28d0da0-3df8-467d-870e-b826d36a4d78,
  abstract     = {{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.}},
  author       = {{Holmkvist, Johan and Cervin, C and Lyssenko, Valeriya and Winckler, W and Anevski, Dragi and Cilio, Corrado and Almgren, Peter and Berglund, Göran and Nilsson, P and Tuomi, Tiinamaija and Lindgren, C and Altshuler, D and Groop, Leif}},
  issn         = {{1432-0428}},
  keywords     = {{insulin; MODY3; prospective studies; type 2 diabetes; mellitus; factor 1-alpha; case-control studies; association study; glucose; hepatocyte nuclear}},
  language     = {{eng}},
  number       = {{Oct 11}},
  pages        = {{2882--2891}},
  publisher    = {{Springer}},
  series       = {{Diabetologia}},
  title        = {{Common variants in HNF-1 alpha and risk of type 2 diabetes.}},
  url          = {{http://dx.doi.org/10.1007/s00125-006-0450-x}},
  doi          = {{10.1007/s00125-006-0450-x}},
  volume       = {{49}},
  year         = {{2006}},
}