Dataset Information

Identification of common variants in the SHBG gene affecting sex hormone-binding globulin levels and breast cancer risk in postmenopausal women.

ABSTRACT: BACKGROUND:Circulating levels of sex hormone-binding globulin (SHBG) are inversely associated with breast cancer risk in postmenopausal women. Three polymorphisms within the SHBG gene have been reported to affect SHBG levels, but there has been no systematic attempt to identify other such variants. METHODS:We looked for associations between SHBG levels in 1,134 healthy, postmenopausal women and 11 tagging single nucleotide polymorphisms (SNP) in or around the SHBG gene. Associations between SHBG SNPs and breast cancer were tested in up to 6,622 postmenopausal breast cancer cases and 6,784 controls. RESULTS:Ten SNPs within or close to the SHBG gene were significantly associated with SHBG levels as was the (TAAAA)(n) polymorphism. The best-fitting combination of rs6259, rs858521, and rs727428 and body mass index, waist, hip, age, and smoking status accounted for 24% of the variance in SHBG levels (natural logarithm transformed). Haplotype analysis suggested that rs858518, rs727428, or a variant in linkage disequilibrium with them acts to decrease SHBG levels but that this effect is neutralized by rs6259 (D356N). rs1799941 increases SHBG levels, but the previously reported association with (TAAAA)(n) repeat length appears to be a consequence of linkage disequilibrium with these SNPs. One further SHBG SNP was significantly associated with breast cancer (rs6257, per-allele odds ratio, 0.88; 95% confidence interval, 0.82-0.95; P = 0.002). CONCLUSION:At least 3 SNPs showed associations with SHBG levels that were highly significant but relatively small in magnitude. rs6257 is a potential breast cancer susceptibility variant, but relationships between the genetic determinants of SHBG levels and breast cancer are complex.

SUBMITTER: Thompson DJ

PROVIDER: S-EPMC2660245 | biostudies-literature | 2008 Dec

REPOSITORIES: biostudies-literature

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Identification of common variants in the SHBG gene affecting sex hormone-binding globulin levels and breast cancer risk in postmenopausal women.

Thompson Deborah J DJ Healey Catherine S CS Baynes Caroline C Kalmyrzaev Bolot B Ahmed Shahana S Dowsett Mitch M Folkerd Elizabeth E Luben Robert N RN Cox David D Ballinger Dennis D Pharoah Paul D P PD Ponder Bruce A J BA Dunning Alison M AM Easton Douglas F DF

Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 20081201 12

<h4>Background</h4>Circulating levels of sex hormone-binding globulin (SHBG) are inversely associated with breast cancer risk in postmenopausal women. Three polymorphisms within the SHBG gene have been reported to affect SHBG levels, but there has been no systematic attempt to identify other such variants.<h4>Methods</h4>We looked for associations between SHBG levels in 1,134 healthy, postmenopausal women and 11 tagging single nucleotide polymorphisms (SNP) in or around the SHBG gene. Associatio ...[more]

PMID: 19064566

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Project description:Essentials Endogenous hormone levels' influence on hemostatic factor levels is not fully characterized. We tested for associations of endogenous hormone with hemostatic factor levels in postmenopause. Estrone levels were inversely associated with the natural anticoagulant, protein S antigen. Dehydroepiandrosterone sulfate levels were inversely associated with thrombin generation.SummaryBackground Oral use of exogenous estrogen/progestin alters hemostatic factor levels. The influence of endogenous hormones on these levels is incompletely characterized. Objectives Our study aimed to test whether, among postmenopausal women, high levels of estradiol (E2), estrone (E1), testosterone (T), dehydroepiandrosterone sulfate (DHEAS), dehydroepiandrosterone (DHEA), and androstenedione, and low levels of sex hormone-binding globulin (SHBG), are positively associated with measures of thrombin generation (TG), a normalized activated protein C sensitivity ratio (nAPCsr), and factor VII activity (FVIIc), and negatively associated with antithrombin activity (ATc) and total protein S antigen (PSAg). Methods This Heart and Vascular Health study cross-sectional analysis included 131 postmenopausal women without a prior venous thrombosis who were not currently using hormone therapy. Adjusted mean differences in TG, nAPCsr, FVIIc, ATc and PSAg levels associated with differences in hormone levels were estimated using multiple linear regression. We measured E2, E1, total T, DHEAS, DHEA and androstenedione levels by mass spectrometry, SHBG levels by immunoassay, and calculated the level of free T. Results One picogram per milliliter higher E1 levels were associated with 0.24% lower PSAg levels (95% Confidence Interval [CI]: -0.35, -0.12) and 1 μg mL-1 higher DHEAS levels were associated with 40.8 nm lower TG peak values (95% CI: -59.5, -22.2) and 140.7 nm×min lower TG endogenous thrombin potential (ETP) (95% CI: -212.1, -69.4). After multiple comparisons correction, there was no evidence for other associations. Conclusions As hypothesized, higher E1 levels were associated with lower levels of the natural anticoagulant PSAg. Contrary to hypotheses, higher DHEAS levels were associated with differences in TG peak and ETP that suggest less generation of thrombin.

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.

Dataset Information

Identification of common variants in the SHBG gene affecting sex hormone-binding globulin levels and breast cancer risk in postmenopausal women.

Publications

Identification of common variants in the SHBG gene affecting sex hormone-binding globulin levels and breast cancer risk in postmenopausal women.

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