Author: Perry John R.B. Weedon Michael N. Langenberg Claudia Jackson Anne U. Lyssenko Valeriya Spars Thomas Thorleifsson Gudmar Grallert Harald Ferrucci Luigi Maggio Marcello Paolisso Giuseppe Walker Mark Palmer Colin N.A. Payne Felicity Young Elizabeth Herder Christian Narisu Narisu Morken Mario A. Bonnycastle Lori L. Owen Katharine R. Shields Beverley Knight Beatrice Bennett Amanda Groves Christopher J. Ruokonen Aimo Jarvelin Marjo Riitta Pearson Ewan Pascoe Laura Ferrannini Ele Bornstein Stefan R. Stringham Heather M. Scott Laura J. Kuusisto Johanna Nilsson Peter Neptin Malin Gjesing Anette P. Pisinger Charlotta Lauritzen Torsten Sandbaek Annelli Sampson Mike Zeggini MAGIC- Ele Lindgren Cecilia M. Steinthorsdottir Valgerdur Thorsteinsdottir Unnur Hansen Torben Schwarz Peter Illig Thomas Laakso Markku Stefansson Kari Morris Andrew D. Groop Leif Pedersen Oluf Boehnke Michael Barroso Ins Wareham Nicholas J. Hattersley Andrew T. McCarthy Mark I. Frayling Timothy M.
Publisher: Oxford University Press
ISSN: 1460-2083
Source: Human Molecular Genetics, Vol.19, Iss.3, 2010-02, pp. : 535-544
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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 2 105], 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.
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