@article{Zeggini (2009, 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 = {Zeggini (, ) E and Perry, John R. B. and Jr., Perry ( and Weedon, Michael N. and ) Mn, Weedon ( and Langenberg, Claudia and Langenberg (, ) C and Jackson, Anne U. and ) Au, Jackson ( and Lyssenko, Valeriya and Lyssenko (, ) V and Sparso, Thomas and Sparsø (, ) T and Thorleifsson, Gudmar and Thorleifsson (, ) G and Grallert, Harald and Grallert (, ) H and Ferrucci, Luigi and Ferrucci (, ) L and Maggio, Marcello and Maggio (, ) M and Paolisso, Giuseppe and Paolisso (, ) G and Walker, Mark and Walker (, ) M and Palmer, Colin N. A. and ) Cn, Palmer ( and Payne, Felicity and Payne, F. and Payne, ) F and Young, Elizabeth and Young (, E. and Herder, Christian and Herder, C. and Herder, ) C and Narisu, Narisu and Narisu (, N. and Morken, Mario A. and ) Ma, Morken and Bonnycastle, Lori L. and Bonnycastle (, L. L. and Owen, Katharine R. and ) Kr, Owen ( and Shields, Beverley and Shields (, ) B and Knight (, ) B and Knight, Beatrice and Bennett (, ) A and Bennett, Amanda and ) Cj, Groves ( and Groves, Christopher J. and Ruokonen (, ) A and Ruokonen, Aimo and ) Mr, Jarvelin( and Jarvelin, Marjo Riitta and Pearson (, ) E and Pearson, Ewan and Pascoe (, ) L and Pascoe, Laura and Ferrannini (, ) E and Ferrannini, Ele and ) Sr, Bornstein ( and Bornstein, Stefan R. and ) Hm, Stringham ( and Stringham, Heather M. and ) Lj, Scott ( and Scott, Laura J. and Kuusisto (, ) J and Kuusisto, Johanna and Nilsson (, ) P and Nilsson, Peter and Neptin (, ) M and Neptin, Malin and ) Ap, Gjesing ( and Gjesing, Anette P. and Pisinger, Charlotta and Pisinger (, ) C and Lauritzen, Torsten and Lauritzen (, ) T and Sandbaek (, ) A and Sandbaek, Annelli and Magic (, ) M Sampson and Sampson, Mike and Zeggini, MAGIC Ele and Magic, Ele Zeggini and ) Cm, Lindgren ( and Lindgren, Cecilia M. and Steinthorsdottir (, ) V and Steinthorsdottir, Valgerdur and Thorsteinsdottir (, ) U and Thorsteinsdottir, Unnur and Hansen (, ) T and Hansen, Torben and Schwarz (, ) P and Schwarz, Peter and Illig (, ) T and Illig, Thomas and Laakso (, ) M and Laakso, Markku and Stefansson (, ) K and Stefansson, Kari and ) Ad, Morris ( and Morris, Andrew D. and Groop (, ) L and Groop, Leif and Pedersen (, ) O and Pedersen, Oluf and Boehnke (, ) M and Boehnke, Michael and Barroso (, ) I and Barroso, Ines and ) Nj, Wareham ( and Wareham, Nicholas J. and ) At, Hattersley ( and Hattersley, Andrew T. and ) Mi, McCarthy ( and McCarthy, Mark I. and ) Tm, Frayling and Frayling, Timothy M.}, doi = {10.1093/hmg/ddp522}, journal = {Human Molecular Genetics}, month = {nov}, pages = {535-544}, title = {Genetic evidence that raised sex hormone binding globulin (SHBG) levels reduce the risk of type 2 diabetes.}, url = {https://academic.oup.com/hmg/article-pdf/19/3/535/17251164/ddp522.pdf}, volume = {19}, year = {2009} }