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

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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