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

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.

SUBMITTER: Perry JR

PROVIDER: S-EPMC2798726 | biostudies-literature | 2010 Feb

REPOSITORIES: biostudies-literature

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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 JR Weedon Michael N MN Langenberg Claudia C Jackson Anne U AU Lyssenko Valeriya V Sparsø Thomas T Thorleifsson Gudmar G Grallert Harald H Ferrucci Luigi L Maggio Marcello M Paolisso Giuseppe G Walker Mark M Palmer Colin N A CN Payne Felicity F Young Elizabeth E Herder Christian C Narisu Narisu N Morken Mario A MA Bonnycastle Lori L LL Owen Katharine R KR Shields Beverley B Knight Beatrice B Bennett Amanda A Groves Christopher J CJ Ruokonen Aimo A Jarvelin Marjo Riitta MR Pearson Ewan E Pascoe Laura L Ferrannini Ele E Bornstein Stefan R SR Stringham Heather M HM Scott Laura J LJ Kuusisto Johanna J Nilsson Peter P Neptin Malin M Gjesing Anette P AP Pisinger Charlotta C Lauritzen Torsten T Sandbaek Annelli A Sampson Mike M Zeggini Ele E Lindgren Cecilia M CM Steinthorsdottir Valgerdur V Thorsteinsdottir Unnur U Hansen Torben T Schwarz Peter P Illig Thomas T Laakso Markku M Stefansson Kari K Morris Andrew D AD Groop Leif L Pedersen Oluf O Boehnke Michael M Barroso Inês I Wareham Nicholas J NJ Hattersley Andrew T AT McCarthy Mark I MI Frayling Timothy M TM

Human molecular genetics 20091118 3

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 p ...[more]

PMID: 19933169

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Project description:Background and Purpose- Circulating levels of SHBG (sex hormone-binding globulin) have been inversely linked to obesity, diabetes mellitus, and other cardiometabolic disorders. It remains uncertain whether low SHBG is prospectively predictive of stroke risk, particularly in women. We investigated whether SHBG is associated with risk of incident ischemic stroke (IS) among women in the WHI (Women's Health Initiative). Methods- From an observational cohort of 161 808 postmenopausal women enrolled in the WHI at 40 sites across the United States from 1993 to 1998, we identified 13 192 participants free of prevalent stroke at baseline who were included in an ancillary study that measured serum SHBG. We used Cox proportional hazards regression, stratified by SHBG measurement assay, to assess IS risk across quintiles of SHBG (Q1-Q5), adjusting first for demographic variables (model 1), additionally for body mass index, hypertension, alcohol use, and smoking status (model 2), and for physical activity and reproductive risk factors (model 3). In sensitivity analyses, potential mediators (diabetes mellitus status, levels of estradiol, testosterone, and CRP [C-reactive protein]) were included. Results- Of 13 192 participants (mean age, 62.5 years; 67.4% non-Hispanic white, 18.5% black, 7.6% Hispanic, and 5.0% Asian), after following for an average of 11.6 years, 768 IS events were adjudicated. Compared with the highest quintile of SHBG levels (referent), women in the lowest SHBG quintile had a higher risk of IS in all 3 multivariable models (model 1: hazard ratio, 1.88 [95% CI, 1.47-2.41]; model 2: hazard ratio, 1.69 [95% CI, 1.30-2.20]; model 3: hazard ratio, 1.61 [95% CI, 1.19-2.19]; trend tests P<0.05 for all models). Including potential mediators such as diabetes mellitus, estradiol, and testosterone in the models attenuated but did not eliminate significant inverse associations between SHBG and IS. Conclusions- In this prospective cohort of postmenopausal women, there was a statistically significant inverse association between serum SHBG levels and IS risk, which supports the notion that SHBG could be used as a risk stratification tool for predicting IS in women.

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

Publications

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

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