Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Meta-Analysis
. 2010 Feb 1;19(3):535-44.
doi: 10.1093/hmg/ddp522. Epub 2009 Nov 18.

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

John R B Perry  1 , Michael N Weedon, Claudia Langenberg, Anne U Jackson, Valeriya Lyssenko, Thomas Sparsø, Gudmar Thorleifsson, Harald Grallert, Luigi Ferrucci, Marcello Maggio, Giuseppe Paolisso, Mark Walker, Colin N A Palmer, Felicity Payne, Elizabeth Young, Christian Herder, Narisu Narisu, Mario A Morken, Lori L Bonnycastle, Katharine R Owen, Beverley Shields, Beatrice Knight, Amanda Bennett, Christopher J Groves, Aimo Ruokonen, Marjo Riitta Jarvelin, Ewan Pearson, Laura Pascoe, Ele Ferrannini, Stefan R Bornstein, Heather M Stringham, Laura J Scott, Johanna Kuusisto, Peter Nilsson, Malin Neptin, Anette P Gjesing, Charlotta Pisinger, Torsten Lauritzen, Annelli Sandbaek, Mike Sampson; MAGIC; Ele Zeggini, Cecilia M Lindgren, Valgerdur Steinthorsdottir, Unnur Thorsteinsdottir, Torben Hansen, Peter Schwarz, Thomas Illig, Markku Laakso, Kari Stefansson, Andrew D Morris, Leif Groop, Oluf Pedersen, Michael Boehnke, Inês Barroso, Nicholas J Wareham, Andrew T Hattersley, Mark I McCarthy, Timothy M Frayling
Affiliations
Meta-Analysis

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

John R B Perry et al. Hum Mol Genet. .

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.

PubMed Disclaimer

Figures

Figure 1.
Figure 1.
Triangulation approach to assess how the observed association of the SHBG SNP rs1799941 with type 2 diabetes compares with that expected given the association between rs1799941 and circulating SHBG levels and the difference in SHBG levels between type 2 diabetes patients and controls.
Figure 2.
Figure 2.
Meta-analysis of rs1799941 in type 2 diabetes case–control studies correcting for or matching for BMI, age and sex. OR, odds ratio.
Figure 3.
Figure 3.
Details of the correlations between SHBG levels and type 2 diabetes from seven cross-sectional studies of European individuals correcting or matching for BMI or waist circumference.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Ding E.L., Song Y., Malik V.S., Liu S. Sex differences of endogenous sex hormones and risk of type 2 diabetes: a systematic review and meta-analysis. JAMA. 2006;295:1288–1299. - PubMed
    1. Ding E.L., Song Y., Manson J.E., Hunter D.J., Lee C.C., Rifai N., Buring J.E., Gaziano J.M., Liu S. Sex hormone-binding globulin and risk of type 2 diabetes in women and men. N. Engl. J. Med. 2009;361:1152–1163. - PMC - PubMed
    1. Dunaif A. Hyperandrogenic anovulation (PCOS): a unique disorder of insulin action associated with an increased risk of non-insulin-dependent diabetes mellitus. Am. J. Med. 1995;98:33S–39S. - PubMed
    1. Marin P., Holmang S., Jonsson L., Sjostrom L., Kvist H., Holm G., Lindstedt G., Bjorntorp P. The effects of testosterone treatment on body composition and metabolism in middle-aged obese men. Int. J. Obes. Relat. Metab. Disord. 1992;16:991–997. - PubMed
    1. Simon D., Charles M.A., Lahlou N., Nahoul K., Oppert J.M., Gouault-Heilmann M., Lemort N., Thibult N., Joubert E., Balkau B., et al. Androgen therapy improves insulin sensitivity and decreases leptin level in healthy adult men with low plasma total testosterone: a 3-month randomized placebo-controlled trial. Diabetes Care. 2001;24:2149–2151. - PubMed

Publication types

Substances