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Association of common variation in the HNF1 alpha gene region with risk of type 2 diabetes

Winckler, W; Burtt, N P; Holmkvist, Johan LU ; Cervin, Camilla LU ; de Bakker, P I W; Sun, M; Almgren, Peter LU ; Tuomi, T; Gaudet, D and Hudson, T J, et al. (2005) In Diabetes 54(8). p.2336-2342
Abstract
It is currently unclear how often genes that are mutated to cause rare, early-onset monogenic forms of disease also harbor common variants that contribute to the more typical polygenic form of each disease. The gene for MODY3 diabetes, HNF1 alpha, lies in a region that has shown linkage to late-onset type 2 diabetes (12q24, NIDDM2), and previous association studies have suggested a weak trend toward association for common missense variants in HNF1a with glucose-related traits. Based on genotyping of 79 common SNPs in the 118 kb spanning HNF1 alpha, we selected 21 haplotype tag single nucleotide polymorphisms (SNPs) and genotyped them in > 4,000 diabetic patients and control subjects from Sweden, Finland, and Canada. Several SNPs from... (More)
It is currently unclear how often genes that are mutated to cause rare, early-onset monogenic forms of disease also harbor common variants that contribute to the more typical polygenic form of each disease. The gene for MODY3 diabetes, HNF1 alpha, lies in a region that has shown linkage to late-onset type 2 diabetes (12q24, NIDDM2), and previous association studies have suggested a weak trend toward association for common missense variants in HNF1a with glucose-related traits. Based on genotyping of 79 common SNPs in the 118 kb spanning HNF1 alpha, we selected 21 haplotype tag single nucleotide polymorphisms (SNPs) and genotyped them in > 4,000 diabetic patients and control subjects from Sweden, Finland, and Canada. Several SNPs from the coding region and 5' of the gene demonstrated nominal association with type 2 diabetes, with the most significant marker (rs1920792) having an odds ratio of 1.17 and a P value of 0.002. We then genotyped three SNPs with the strongest evidence for association to type 2 diabetes (rs1920792, I27L, and A98V) in an additional 4,400 type 2 diabetic and control subjects from North America and Poland and compared our results with those of the original sample and of Weedon et al. None of the results were consistently observed across all samples, with the possible exception of a modest association of the rare (3-5%) A98V variant. These results indicate that common variants in HNF1 alpha either play no role in type 2 diabetes, a very small role, or a role that cannot be consistently observed without consideration of as yet unmeasured genetic or environmental modifiers. (Less)
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Contribution to journal
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Diabetes
volume
54
issue
8
pages
2336 - 2342
publisher
American Diabetes Association Inc.
external identifiers
  • pmid:16046299
  • wos:000230869500009
  • scopus:23644442564
ISSN
1939-327X
language
English
LU publication?
yes
id
e6eeef9c-1c9c-483a-877e-8cca21938a2c (old id 231636)
alternative location
http://diabetes.diabetesjournals.org/cgi/reprint/54/8/2336
date added to LUP
2007-08-06 12:48:25
date last changed
2017-02-19 04:18:21
@article{e6eeef9c-1c9c-483a-877e-8cca21938a2c,
  abstract     = {It is currently unclear how often genes that are mutated to cause rare, early-onset monogenic forms of disease also harbor common variants that contribute to the more typical polygenic form of each disease. The gene for MODY3 diabetes, HNF1 alpha, lies in a region that has shown linkage to late-onset type 2 diabetes (12q24, NIDDM2), and previous association studies have suggested a weak trend toward association for common missense variants in HNF1a with glucose-related traits. Based on genotyping of 79 common SNPs in the 118 kb spanning HNF1 alpha, we selected 21 haplotype tag single nucleotide polymorphisms (SNPs) and genotyped them in > 4,000 diabetic patients and control subjects from Sweden, Finland, and Canada. Several SNPs from the coding region and 5' of the gene demonstrated nominal association with type 2 diabetes, with the most significant marker (rs1920792) having an odds ratio of 1.17 and a P value of 0.002. We then genotyped three SNPs with the strongest evidence for association to type 2 diabetes (rs1920792, I27L, and A98V) in an additional 4,400 type 2 diabetic and control subjects from North America and Poland and compared our results with those of the original sample and of Weedon et al. None of the results were consistently observed across all samples, with the possible exception of a modest association of the rare (3-5%) A98V variant. These results indicate that common variants in HNF1 alpha either play no role in type 2 diabetes, a very small role, or a role that cannot be consistently observed without consideration of as yet unmeasured genetic or environmental modifiers.},
  author       = {Winckler, W and Burtt, N P and Holmkvist, Johan and Cervin, Camilla and de Bakker, P I W and Sun, M and Almgren, Peter and Tuomi, T and Gaudet, D and Hudson, T J and Ardlie, K G and Daly, M J and Hirschhorn, J N and Altshuler, D and Groop, Leif},
  issn         = {1939-327X},
  language     = {eng},
  number       = {8},
  pages        = {2336--2342},
  publisher    = {American Diabetes Association Inc.},
  series       = {Diabetes},
  title        = {Association of common variation in the HNF1 alpha gene region with risk of type 2 diabetes},
  volume       = {54},
  year         = {2005},
}