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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 , 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)
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Contribution to journal
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published
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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
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f28d0da0-3df8-467d-870e-b826d36a4d78 (old id 162369)
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http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=17033837&dopt=Abstract
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2007-07-23 16:45:55
date last changed
2019-07-30 02:05:07
@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},
  keyword      = {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},
  volume       = {49},
  year         = {2006},
}