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Genetic evidence that raised sex hormone binding globulin (SHBG) levels reduce the risk of type 2 diabetes

Perry, John R. B.; Weedon, Michael N.; Langenberg, Claudia; Jackson, Anne U.; Lyssenko, Valeriya; Sparso, Thomas; Thorleifsson, Gudmar; Grallert, Harald; Ferrucci, Luigi and Maggio, Marcello, et al. (2010) In Human Molecular Genetics 19(3). p.535-544
Abstract
Epidemiological studies consistently show that circulating sex hormone binding globulin (SHBG) levels are lower in type 2 diabetes patients than non-diabetic individuals, but the causal nature of this association is controversial. Genetic studies can help dissect causal directions of epidemiological associations because genotypes are much less likely to be confounded, biased or influenced by disease processes. Using this Mendelian randomization principle, we selected a common single nucleotide polymorphism (SNP) near the SHBG gene, rs1799941, that is strongly associated with SHBG levels. We used data from this SNP, or closely correlated SNPs, in 27 657 type 2 diabetes patients and 58 481 controls from 15 studies. We then used data from... (More)
Epidemiological studies consistently show that circulating sex hormone binding globulin (SHBG) levels are lower in type 2 diabetes patients than non-diabetic individuals, but the causal nature of this association is controversial. Genetic studies can help dissect causal directions of epidemiological associations because genotypes are much less likely to be confounded, biased or influenced by disease processes. Using this Mendelian randomization principle, we selected a common single nucleotide polymorphism (SNP) near the SHBG gene, rs1799941, that is strongly associated with SHBG levels. We used data from this SNP, or closely correlated SNPs, in 27 657 type 2 diabetes patients and 58 481 controls from 15 studies. We then used data from additional studies to estimate the difference in SHBG levels between type 2 diabetes patients and controls. The SHBG SNP rs1799941 was associated with type 2 diabetes [odds ratio (OR) 0.94, 95% CI: 0.91, 0.97; P = 2 x 10(-5)], with the SHBG raising allele associated with reduced risk of type 2 diabetes. This effect was very similar to that expected (OR 0.92, 95% CI: 0.88, 0.96), given the SHBG-SNP versus SHBG levels association (SHBG levels are 0.2 standard deviations higher per copy of the A allele) and the SHBG levels versus type 2 diabetes association (SHBG levels are 0.23 standard deviations lower in type 2 diabetic patients compared to controls). Results were very similar in men and women. There was no evidence that this variant is associated with diabetes-related intermediate traits, including several measures of insulin secretion and resistance. Our results, together with those from another recent genetic study, strengthen evidence that SHBG and sex hormones are involved in the aetiology of type 2 diabetes. (Less)
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Human Molecular Genetics
volume
19
issue
3
pages
535 - 544
publisher
Oxford University Press
external identifiers
  • wos:000273227200013
  • scopus:77949911881
ISSN
0964-6906
DOI
10.1093/hmg/ddp522
language
English
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yes
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4eb8830c-976a-4e8d-b426-9faa9b2dba1f (old id 1533689)
date added to LUP
2010-01-27 15:47:03
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2018-06-17 03:10:30
@article{4eb8830c-976a-4e8d-b426-9faa9b2dba1f,
  abstract     = {Epidemiological studies consistently show that circulating sex hormone binding globulin (SHBG) levels are lower in type 2 diabetes patients than non-diabetic individuals, but the causal nature of this association is controversial. Genetic studies can help dissect causal directions of epidemiological associations because genotypes are much less likely to be confounded, biased or influenced by disease processes. Using this Mendelian randomization principle, we selected a common single nucleotide polymorphism (SNP) near the SHBG gene, rs1799941, that is strongly associated with SHBG levels. We used data from this SNP, or closely correlated SNPs, in 27 657 type 2 diabetes patients and 58 481 controls from 15 studies. We then used data from additional studies to estimate the difference in SHBG levels between type 2 diabetes patients and controls. The SHBG SNP rs1799941 was associated with type 2 diabetes [odds ratio (OR) 0.94, 95% CI: 0.91, 0.97; P = 2 x 10(-5)], with the SHBG raising allele associated with reduced risk of type 2 diabetes. This effect was very similar to that expected (OR 0.92, 95% CI: 0.88, 0.96), given the SHBG-SNP versus SHBG levels association (SHBG levels are 0.2 standard deviations higher per copy of the A allele) and the SHBG levels versus type 2 diabetes association (SHBG levels are 0.23 standard deviations lower in type 2 diabetic patients compared to controls). Results were very similar in men and women. There was no evidence that this variant is associated with diabetes-related intermediate traits, including several measures of insulin secretion and resistance. Our results, together with those from another recent genetic study, strengthen evidence that SHBG and sex hormones are involved in the aetiology of type 2 diabetes.},
  author       = {Perry, John R. B. and Weedon, Michael N. and Langenberg, Claudia and Jackson, Anne U. and Lyssenko, Valeriya and Sparso, Thomas and Thorleifsson, Gudmar and Grallert, Harald and Ferrucci, Luigi and Maggio, Marcello and Paolisso, Giuseppe and Walker, Mark and Palmer, Colin N. A. and Payne, Felicity and Young, Elizabeth and Herder, Christian and Narisu, Narisu and Morken, Mario A. and Bonnycastle, Lori L. and Owen, Katharine R. and Shields, Beverley and Knight, Beatrice and Bennett, Amanda and Groves, Christopher J. and Ruokonen, Aimo and Jarvelin, Marjo Riitta and Pearson, Ewan and Pascoe, Laura and Ferrannini, Ele and Bornstein, Stefan R. and Stringham, Heather M. and Scott, Laura J. and Kuusisto, Johanna and Nilsson, Peter and Neptin, Malin and Gjesing, Anette P. and Pisinger, Charlotta and Lauritzen, Torsten and Sandbaek, Annelli and Sampson, Mike and Magic, Ele Zeggini and Lindgren, Cecilia M. and Steinthorsdottir, Valgerdur and Thorsteinsdottir, Unnur and Hansen, Torben and Schwarz, Peter and Illig, Thomas and Laakso, Markku and Stefansson, Kari and Morris, Andrew D. and Groop, Leif and Pedersen, Oluf and Boehnke, Michael and Barroso, Ines and Wareham, Nicholas J. and Hattersley, Andrew T. and McCarthy, Mark I. and Frayling, Timothy M.},
  issn         = {0964-6906},
  language     = {eng},
  number       = {3},
  pages        = {535--544},
  publisher    = {Oxford University Press},
  series       = {Human Molecular Genetics},
  title        = {Genetic evidence that raised sex hormone binding globulin (SHBG) levels reduce the risk of type 2 diabetes},
  url          = {http://dx.doi.org/10.1093/hmg/ddp522},
  volume       = {19},
  year         = {2010},
}