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1.  A Genome-Wide Association Meta-Analysis of Circulating Sex Hormone–Binding Globulin Reveals Multiple Loci Implicated in Sex Steroid Hormone Regulation 
Coviello, Andrea D. | Haring, Robin | Wellons, Melissa | Vaidya, Dhananjay | Lehtimäki, Terho | Keildson, Sarah | Lunetta, Kathryn L. | He, Chunyan | Fornage, Myriam | Lagou, Vasiliki | Mangino, Massimo | Onland-Moret, N. Charlotte | Chen, Brian | Eriksson, Joel | Garcia, Melissa | Liu, Yong Mei | Koster, Annemarie | Lohman, Kurt | Lyytikäinen, Leo-Pekka | Petersen, Ann-Kristin | Prescott, Jennifer | Stolk, Lisette | Vandenput, Liesbeth | Wood, Andrew R. | Zhuang, Wei Vivian | Ruokonen, Aimo | Hartikainen, Anna-Liisa | Pouta, Anneli | Bandinelli, Stefania | Biffar, Reiner | Brabant, Georg | Cox, David G. | Chen, Yuhui | Cummings, Steven | Ferrucci, Luigi | Gunter, Marc J. | Hankinson, Susan E. | Martikainen, Hannu | Hofman, Albert | Homuth, Georg | Illig, Thomas | Jansson, John-Olov | Johnson, Andrew D. | Karasik, David | Karlsson, Magnus | Kettunen, Johannes | Kiel, Douglas P. | Kraft, Peter | Liu, Jingmin | Ljunggren, Östen | Lorentzon, Mattias | Maggio, Marcello | Markus, Marcello R. P. | Mellström, Dan | Miljkovic, Iva | Mirel, Daniel | Nelson, Sarah | Morin Papunen, Laure | Peeters, Petra H. M. | Prokopenko, Inga | Raffel, Leslie | Reincke, Martin | Reiner, Alex P. | Rexrode, Kathryn | Rivadeneira, Fernando | Schwartz, Stephen M. | Siscovick, David | Soranzo, Nicole | Stöckl, Doris | Tworoger, Shelley | Uitterlinden, André G. | van Gils, Carla H. | Vasan, Ramachandran S. | Wichmann, H.-Erich | Zhai, Guangju | Bhasin, Shalender | Bidlingmaier, Martin | Chanock, Stephen J. | De Vivo, Immaculata | Harris, Tamara B. | Hunter, David J. | Kähönen, Mika | Liu, Simin | Ouyang, Pamela | Spector, Tim D. | van der Schouw, Yvonne T. | Viikari, Jorma | Wallaschofski, Henri | McCarthy, Mark I. | Frayling, Timothy M. | Murray, Anna | Franks, Steve | Järvelin, Marjo-Riitta | de Jong, Frank H. | Raitakari, Olli | Teumer, Alexander | Ohlsson, Claes | Murabito, Joanne M. | Perry, John R. B.
PLoS Genetics  2012;8(7):e1002805.
Sex hormone-binding globulin (SHBG) is a glycoprotein responsible for the transport and biologic availability of sex steroid hormones, primarily testosterone and estradiol. SHBG has been associated with chronic diseases including type 2 diabetes (T2D) and with hormone-sensitive cancers such as breast and prostate cancer. We performed a genome-wide association study (GWAS) meta-analysis of 21,791 individuals from 10 epidemiologic studies and validated these findings in 7,046 individuals in an additional six studies. We identified twelve genomic regions (SNPs) associated with circulating SHBG concentrations. Loci near the identified SNPs included SHBG (rs12150660, 17p13.1, p = 1.8×10−106), PRMT6 (rs17496332, 1p13.3, p = 1.4×10−11), GCKR (rs780093, 2p23.3, p = 2.2×10−16), ZBTB10 (rs440837, 8q21.13, p = 3.4×10−09), JMJD1C (rs7910927, 10q21.3, p = 6.1×10−35), SLCO1B1 (rs4149056, 12p12.1, p = 1.9×10−08), NR2F2 (rs8023580, 15q26.2, p = 8.3×10−12), ZNF652 (rs2411984, 17q21.32, p = 3.5×10−14), TDGF3 (rs1573036, Xq22.3, p = 4.1×10−14), LHCGR (rs10454142, 2p16.3, p = 1.3×10−07), BAIAP2L1 (rs3779195, 7q21.3, p = 2.7×10−08), and UGT2B15 (rs293428, 4q13.2, p = 5.5×10−06). These genes encompass multiple biologic pathways, including hepatic function, lipid metabolism, carbohydrate metabolism and T2D, androgen and estrogen receptor function, epigenetic effects, and the biology of sex steroid hormone-responsive cancers including breast and prostate cancer. We found evidence of sex-differentiated genetic influences on SHBG. In a sex-specific GWAS, the loci 4q13.2-UGT2B15 was significant in men only (men p = 2.5×10−08, women p = 0.66, heterogeneity p = 0.003). Additionally, three loci showed strong sex-differentiated effects: 17p13.1-SHBG and Xq22.3-TDGF3 were stronger in men, whereas 8q21.12-ZBTB10 was stronger in women. Conditional analyses identified additional signals at the SHBG gene that together almost double the proportion of variance explained at the locus. Using an independent study of 1,129 individuals, all SNPs identified in the overall or sex-differentiated or conditional analyses explained ∼15.6% and ∼8.4% of the genetic variation of SHBG concentrations in men and women, respectively. The evidence for sex-differentiated effects and allelic heterogeneity highlight the importance of considering these features when estimating complex trait variance.
Author Summary
Sex hormone-binding globulin (SHBG) is the key protein responsible for binding and transporting the sex steroid hormones, testosterone and estradiol, in the circulatory system. SHBG regulates their bioavailability and therefore their effects in the body. SHBG has been linked to chronic diseases including type 2 diabetes and to hormone-sensitive cancers such as breast and prostate cancer. SHBG concentrations are approximately 50% heritable in family studies, suggesting SHBG concentrations are under significant genetic control; yet, little is known about the specific genes that influence SHBG. We conducted a large study of the association of SHBG concentrations with markers in the human genome in ∼22,000 white men and women to determine which loci influence SHBG concentrations. Genes near the identified genomic markers in addition to the SHBG protein coding gene included PRMT6, GCKR, ZBTB10, JMJD1C, SLCO1B1, NR2F2, ZNF652, TDGF3, LHCGR, BAIAP2L1, and UGT2B15. These genes represent a wide range of biologic pathways that may relate to SHBG function and sex steroid hormone biology, including liver function, lipid metabolism, carbohydrate metabolism and type 2 diabetes, and the development and progression of sex steroid hormone-responsive cancers.
doi:10.1371/journal.pgen.1002805
PMCID: PMC3400553  PMID: 22829776
2.  Relationships of Circulating Sex Hormone–Binding Globulin With Metabolic Traits in Humans 
Diabetes  2010;59(12):3167-3173.
OBJECTIVE
Recent data suggested that sex hormone–binding globulin (SHBG) levels decrease when fat accumulates in the liver and that circulating SHBG may be causally involved in the pathogenesis of type 2 diabetes in humans. In the present study, we investigated mechanisms by which high SHBG may prevent development to diabetes.
RESEARCH DESIGN AND METHODS
Before and during a 9-month lifestyle intervention, total body and visceral fat were precisely measured by magnetic resonance (MR) tomography and liver fat was measured by 1H-MR spectroscopy in 225 subjects. Insulin sensitivity was estimated from a 75-g oral glucose tolerance test (ISOGTT) and measured by a euglycemic hyperinsulinemic clamp (ISclamp, n = 172). Insulin secretion was measured during the OGTT and an ivGTT (n = 172).
RESULTS
SHBG levels correlated positively with insulin sensitivity (ISOGTT, P = 0.037; ISclamp, P = 0.057), independently of age, sex, and total body fat. In a multivariate model, these relationships were also significant after additional adjustment for levels of the adipokine adiponectin and the hepatokine fetuin-A (ISOGTT, P = 0.0096; ISclamp, P = 0.029). Adjustment of circulating SHBG for liver fat abolished the relationships of SHBG with insulin sensitivity. In contrast, circulating SHBG correlated negatively with fasting glycemia, before (r = −0.17, P = 0.009) and after (r = −0.14, P = 0.04) adjustment for liver fat. No correlation of circulating SHBG with adjusted insulin secretion was observed (OGTT, P = 0.16; ivGTT, P = 0.35). The SNP rs1799941 in SHBG was associated with circulating SHBG (P ≤ 0.025) but not with metabolic characteristics (all P > 0.18).
CONCLUSIONS
Possible mechanisms by which high circulating SHBG prevents the development of type 2 diabetes involve regulation of fasting glycemia but not alteration of insulin secretory function.
doi:10.2337/db10-0179
PMCID: PMC2992779  PMID: 20841609
3.  Identification of common variants in the SHBG gene affecting sex hormone binding globulin levels and breast cancer risk in postmenopausal women 
Background
Circulating levels of sex hormone-binding globulin (SHBG) are inversely associated with breast cancer risk in post-menopausal 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 1134 healthy, postmenopausal women and 11 tagging single nucleotide polymorphisms (SNPs) in or around the SHBG gene. Associations between SHBG SNPs and breast cancer were tested in up to 6622 post-menopausal breast cancer cases and 6784 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, 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 neutralised 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% CI=0.82-0.95, p=0.002).
Conclusion
At least three 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.
doi:10.1158/1055-9965.EPI-08-0734
PMCID: PMC2660245  PMID: 19064566
hormones; SNPs; SHBG; breast; cancer
4.  Genetic polymorphisms are associated with serum levels of sex hormone binding globulin in postmenopausal women 
BMC Medical Genetics  2008;9:112.
Background
Estrogen activity plays a critical role in bone homeostasis. The serum levels of sex hormone binding globulin (SHBG) influence free estrogen levels and activity on target tissues. The objective of this study was to analyze the influence of common polymorphisms of the SHBG gene on serum SHBG, bone mineral density (BMD), and osteoporotic fractures.
Methods
Four biallelic polymorphisms of the SHBG gene were studied by means of Taqman assays in 753 postmenopausal women. BMD was measured by DXA and serum SHBG was measured by ELISA.
Results
Age, body weight, and two polymorphisms of the SHBG gene (rs6257 and rs1799941 [A/G]) were significantly associated with serum SHBG in unadjusted and age- and weight-adjusted models. Alleles at the rs1799941 locus showed the strongest association with serum SHBG (p = 0.0004). The difference in SHBG levels between women with AA and GG genotypes at the rs1799941 locus was 39%. There were no significant differences in BMD across SHBG genotypes. The genotypes showed similar frequency distributions in control women and women with vertebral or hip fractures.
Conclusion
Some common genetic variants of the SHBG gene, and particularly an A/G polymorphism situated in the 5' region, influence serum SHBG levels. However, a significant association with BMD or osteoporotic fractures has not been demonstrated.
doi:10.1186/1471-2350-9-112
PMCID: PMC2615755  PMID: 19091090
5.  Sex Hormone-Binding Globulin Genetic Variation: Associations with Type 2 Diabetes Mellitus and Polycystic Ovary Syndrome 
Minerva endocrinologica  2010;35(4):271-280.
Sex hormone-binding globulin (SHBG) is the primary plasma transport protein for sex steroid hormones and regulates the bioavailability of these hormones to target tissues. The gene encoding SHBG is complex and any of several polymorphisms in SHBG have been associated with alterations in circulating SHBG levels.
Epidemiological studies have revealed that low plasma SHBG levels are an early indicator of insulin resistance and predict the development of type 2 diabetes mellitus (T2DM) in both men and women. Although associations between low SHBG levels and risk of diabetes could be explained by the observation that elevations in insulin suppress hepatic SHBG production, recent studies documenting that the transmission of SHBG-altering polymorphisms are associated with risk of T2DM suggest that SHBG may have a more direct physiologic role in glucose homeostasis. However, the exact mechanism(s) underlying this association is not known.
Non-diabetic women with the polycystic ovary syndrome (PCOS), a common endocrine disorder that is associated with insulin resistance, similarly demonstrate lower levels of SHBG. In light of studies investigating polymorphisms in SHBG and T2DM, our group and others have hypothesized that SHBG may represent a candidate gene for PCOS. In this manuscript, we review studies investigating the association between SHBG polymorphisms and PCOS. In summary, multiple studies in women with PCOS confirm that certain genetic polymorphisms are associated with circulating SHBG levels, but they are not consistently associated with PCOS per se.
PMCID: PMC3683392  PMID: 21178921
genetic polymorphisms; polycystic ovary syndrome; sex hormone binding globulin; type 2 diabetes mellitus
6.  Sex Hormone–Binding Globulin and Risk of Type 2 Diabetes in Women and Men 
The New England journal of medicine  2009;361(12):1152-1163.
BACKGROUND
Circulating sex hormone–binding globulin levels are inversely associated with insulin resistance, but whether these levels can predict the risk of developing type 2 diabetes is uncertain.
METHODS
We performed a nested case–control study of postmenopausal women in the Women’s Health Study who were not using hormone therapy (359 with newly diagnosed type 2 diabetes and 359 controls). Plasma levels of sex hormone–binding globulin were measured; two polymorphisms of the gene encoding sex hormone–binding globulin, SHBG, that were robustly associated with the protein levels were genotyped and applied in mendelian randomization analyses. We then conducted a replication study in an independent cohort of men from the Physicians’ Health Study II (170 with newly diagnosed type 2 diabetes and 170 controls).
RESULTS
Among women, higher plasma levels of sex hormone–binding globulin were prospectively associated with a lower risk of type 2 diabetes: multivariable odds ratios were 1.00 for the first (lowest) quartile of plasma levels, 0.16 (95% confidence interval [CI], 0.08 to 0.33) for the second quartile, 0.04 (95% CI, 0.01 to 0.12) for the third quartile, and 0.09 (95% CI, 0.03 to 0.21) for the fourth (highest) quartile (P<0.001 for trend). These prospective associations were replicated among men (odds ratio for the highest quartile of plasma levels vs. the lowest quartile, 0.10; 95% CI, 0.03 to 0.36; P<0.001 for trend). As compared with homozygotes of the respective wild-type allele, carriers of a variant allele of the SHBG single-nucleotide polymorphism (SNP) rs6259 had 10% higher sex hormone–binding globulin levels (P = 0.005), and carriers of an rs6257 variant had 10% lower plasma levels (P = 0.004); variants of both SNPs were also associated with a risk of type 2 diabetes in directions corresponding to their associated sex hormone–binding globulin levels. In mendelian randomization analyses, the predicted odds ratio of type 2 diabetes per standard-deviation increase in the plasma level of sex hormone–binding globulin was 0.28 (95% CI, 0.13 to 0.58) among women and 0.29 (95% CI, 0.15 to 0.58) among men, a finding that suggests that sex hormone–binding globulin may have a causal role in the risk of type 2 diabetes.
CONCLUSIONS
Low circulating levels of sex hormone–binding globulin are a strong predictor of the risk of type 2 diabetes in women and men. The clinical usefulness of both SHBG genotypes and plasma levels in stratification and intervention for the risk of type 2 diabetes warrants further examination.
doi:10.1056/NEJMoa0804381
PMCID: PMC2774225  PMID: 19657112
7.  Potential Role of Tumor Necrosis Factor-α in Downregulating Sex Hormone–Binding Globulin 
Diabetes  2012;61(2):372-382.
Low plasma sex hormone–binding globulin (SHBG) levels are associated with obesity and predict the development of type 2 diabetes. The reason why obese individuals have low circulating SHBG has been attributed to hyperinsulinemia, but no mechanistic evidence has been described. The aim of the current study is to explore whether tumor necrosis factor-α (TNF-α) rather than insulin could be the main factor accounting for low SHBG levels in obesity. We performed in vitro and in vivo studies using human HepG2 cells and human SHBG transgenic mice. In addition, a cross-sectional study to explore the relationship between TNF-α and SHBG in obese patients and an interventional study to examine the effect of insulin administration on circulating SHBG in type 2 diabetic patients were performed. We provide evidence that TNF-α, but not insulin, is the main factor by which SHBG is reduced in obesity. Plasma SHBG was significantly increased rather than decreased after insulin treatment in diabetic patients. TNF-α–induced reduction of SHBG expression was mediated by downregulating HNF4A. Finally, a negative and independent correlation was found between plasma TNF-α receptor 1 and SHBG levels in obese patients. Our results suggest that TNF-α plays an important role downregulating SHBG in chronic low-grade inflammatory diseases such as obesity and type 2 diabetes.
doi:10.2337/db11-0727
PMCID: PMC3266423  PMID: 22210320
8.  Coffee and Caffeine Consumption in Relation to Sex Hormone–Binding Globulin and Risk of Type 2 Diabetes in Postmenopausal Women 
Diabetes  2010;60(1):269-275.
OBJECTIVE
Coffee consumption has been inversely associated with type 2 diabetes risk, but its mechanisms are largely unknown. We aimed to examine whether plasma levels of sex hormones and sex hormone–binding globulin (SHBG) may account for the inverse association between coffee consumption and type 2 diabetes risk.
RESEARCH DESIGN AND METHODS
We conducted a case-control study nested in the prospective Women's Health Study (WHS). During a median follow-up of 10 years, 359 postmenopausal women with newly diagnosed type 2 diabetes were matched with 359 control subjects by age, race, duration of follow-up, and time of blood draw.
RESULTS
Caffeinated coffee was positively associated with SHBG but not with sex hormones. Multivariable-adjusted geometric mean levels of SHBG were 26.6 nmol/l among women consuming ≥4 cups/day of caffeinated coffee and 23.0 nmol/l among nondrinkers (P for trend = 0.01). In contrast, neither decaffeinated coffee nor tea was associated with SHBG or sex hormones. The multivariable-adjusted odds ratio (OR) of type 2 diabetes for women consuming ≥4 cups/day of caffeinated coffee compared with nondrinkers was 0.47 (95% CI 0.23–0.94; P for trend = 0.047). The association was largely attenuated after further adjusting for SHBG (OR 0.71 [95% CI 0.31–1.61]; P for trend = 0.47). In addition, carriers of rs6259 minor allele and noncarriers of rs6257 minor allele of SHBG gene consuming ≥2 cups/day of caffeinated coffee had lower risk of type 2 diabetes in directions corresponding to their associated SHBG.
CONCLUSIONS
Our findings suggest that SHBG may account for the inverse association between coffee consumption and type 2 diabetes risk among postmenopausal women.
doi:10.2337/db10-1193
PMCID: PMC3012180  PMID: 21030499
9.  Genetic Determinants of Serum Testosterone Concentrations in Men 
PLoS Genetics  2011;7(10):e1002313.
Testosterone concentrations in men are associated with cardiovascular morbidity, osteoporosis, and mortality and are affected by age, smoking, and obesity. Because of serum testosterone's high heritability, we performed a meta-analysis of genome-wide association data in 8,938 men from seven cohorts and followed up the genome-wide significant findings in one in silico (n = 871) and two de novo replication cohorts (n = 4,620) to identify genetic loci significantly associated with serum testosterone concentration in men. All these loci were also associated with low serum testosterone concentration defined as <300 ng/dl. Two single-nucleotide polymorphisms at the sex hormone-binding globulin (SHBG) locus (17p13-p12) were identified as independently associated with serum testosterone concentration (rs12150660, p = 1.2×10−41 and rs6258, p = 2.3×10−22). Subjects with ≥3 risk alleles of these variants had 6.5-fold higher risk of having low serum testosterone than subjects with no risk allele. The rs5934505 polymorphism near FAM9B on the X chromosome was also associated with testosterone concentrations (p = 5.6×10−16). The rs6258 polymorphism in exon 4 of SHBG affected SHBG's affinity for binding testosterone and the measured free testosterone fraction (p<0.01). Genetic variants in the SHBG locus and on the X chromosome are associated with a substantial variation in testosterone concentrations and increased risk of low testosterone. rs6258 is the first reported SHBG polymorphism, which affects testosterone binding to SHBG and the free testosterone fraction and could therefore influence the calculation of free testosterone using law-of-mass-action equation.
Author Summary
Testosterone is the most important testicular androgen in men. Low serum testosterone concentrations are associated with cardiovascular morbidity, metabolic syndrome, type 2 diabetes mellitus, atherosclerosis, osteoporosis, sarcopenia, and increased mortality risk. Thus, there is growing evidence that serum testosterone is a valuable biomarker of men's overall health status. Studies in male twins indicate that there is a strong heritability of serum testosterone. Here we perform a large-scale genome-wide association study to examine the effects of common genetic variants on serum testosterone concentrations. By examining 14,429 men, we show that genetic variants in the sex hormone-binding globulin (SHBG) locus and on the X chromosome are associated with a substantial variation in serum testosterone concentrations and increased risk of low testosterone. The reported associations may now be used in order to better understand the functional background of recently identified disease associations related to low testosterone. Importantly, we identified the first known genetic variant, which affects SHBG's affinity for binding testosterone and the free testosterone fraction and could therefore influence the calculation of free testosterone. This finding suggests that individual-based SHBG-testosterone affinity constants are required depending on the genotype of this single-nucleotide polymorphism.
doi:10.1371/journal.pgen.1002313
PMCID: PMC3188559  PMID: 21998597
10.  Ovarian cancer risk and common variation in the sex hormone-binding globulin gene: a population-based case-control study 
BMC Cancer  2007;7:60.
Background
The sex hormone-binding globulin (SHBG) is a carrier protein that modulates the bio-availability of serum sex steroid hormones, which may be involved in ovarian cancer. We evaluated whether common genetic variation in SHBG and its 3' neighbor ATP1B2, in linkage disequilibrium, is associated with the risk of epithelial ovarian cancer.
Methods
The study population included 264 women with ovarian carcinoma and 625 controls participating in a population-based case-control study in Poland. Five common single nucleotide polymorphisms (SNPs) in SHGB and five in ATP1B2 were selected to capture most common variation in this region.
Results
None of the SNPs evaluated was significantly associated with ovarian cancer risk, including the putative functional SNPs SHBG D356N (rs6259) and -67G>A 5'UTR (rs1799941). However, our data were consistent with a decreased ovarian cancer risk associated with the variant alleles for these two SNPs, which have been previously associated with increased circulating levels of SHBG.
Conclusion
These data do not support a substantial association between common genetic variation in SHBG and ovarian cancer risk.
doi:10.1186/1471-2407-7-60
PMCID: PMC1855931  PMID: 17411440
11.  Effects of Polymorphisms of the Sex Hormone-Binding Globulin (SHBG) Gene on Free Estradiol and Bone Mineral Density 
Bone  2009;45(6):1169-1174.
Background
Polymorphisms of the sex hormone binding globulin (SHBG) gene are associated with differences in SHBG levels, influencing the risk for breast cancer and polycystic ovarian syndrome, but no association has been reported for osteoporosis in post-menopausal women.
Objective
To determine the effect of G to A substitution in the 5′UTR (rs1799941) and the Asp356Asn (rs6259) polymorphisms of the SHBG gene on bone mineral density (BMD).
Methods
This is a cross-sectional study in a university-based research center from May, 2002 to December, 2007. A total of two hundred and thirteen healthy postmenopausal Caucasian women > one year from last menstrual period participated to this study. Serum estradiol by ultrasensitive radioimmnunoassay, serum sex hormone-binding globulin by immunoradiometric assay, and urinary NTx by enzyme-linked immunoassay were measured. BMD measurements were performed by dual energy X-ray absorptiometry and genotyping by Pyrosequencing.
Results
There were no significant differences in SHBG levels associated with either rs1799941 or rs6259. Using a p value of <0.00625 for significance, we found that subjects with the A allele (GA+AA) for the rs1799941, had a trend for lower free estradiol index (FEI) compared to the GG genotype (p=0.04). They also had significantly lower BMD at the intertrochanter (p=0.003) and trend for lower BMD at the total hip (p=0.02). There was no significant difference in FEI levels between the genotypes for the rs6259 polymorphism, but women with the Asn allele (Asp/ Asn+Asn/Asn), had significantly lower BMD in the total femur (p=0.004) and intertrochanter (0.002) compared to those with the Asp/Asp genotype.
Conclusions
Our data suggest that polymorphisms of the SHBG gene are associated with significant differences in BMD at the proximal femur sites. Thus, genetic variations in the SHBG gene may influence BMD at the hip in postmenopausal women.
doi:10.1016/j.bone.2009.08.001
PMCID: PMC3689651  PMID: 19679209
sex hormone-binding globulin; free estradiol; bone mineral density; osteoporosis
12.  Quantitative trait loci predicting circulating sex steroid hormones in men from the NCI-Breast and Prostate Cancer Cohort Consortium (BPC3) 
Human Molecular Genetics  2009;18(19):3749-3757.
Twin studies suggest a heritable component to circulating sex steroid hormones and sex hormone-binding globulin (SHBG). In the NCI-Breast and Prostate Cancer Cohort Consortium, 874 SNPs in 37 candidate genes in the sex steroid hormone pathway were examined in relation to circulating levels of SHBG (N = 4720), testosterone (N = 4678), 3α-androstanediol-glucuronide (N = 4767) and 17β-estradiol (N = 2014) in Caucasian men. rs1799941 in SHBG is highly significantly associated with circulating levels of SHBG (P = 4.52 × 10−21), consistent with previous studies, and testosterone (P = 7.54 × 10−15), with mean difference of 26.9 and 14.3%, respectively, comparing wild-type to homozygous variant carriers. Further noteworthy novel findings were observed between SNPs in ESR1 with testosterone levels (rs722208, mean difference = 8.8%, P = 7.37 × 10−6) and SRD5A2 with 3α-androstanediol-glucuronide (rs2208532, mean difference = 11.8%, P = 1.82 × 10−6). Genetic variation in genes in the sex steroid hormone pathway is associated with differences in circulating SHBG and sex steroid hormones.
doi:10.1093/hmg/ddp302
PMCID: PMC2742399  PMID: 19574343
13.  Association of hormonal dysregulation with metabolic syndrome in older women: data from the InCHIANTI study 
Metabolic syndrome (MetS) is a strong risk factor for type 2 diabetes and cardiovascular disease. Conditions associated with hyperandrogenism are often associated with glucose intolerance and other features of MetS in young women. As the prevalence of MetS increases with age and is probably multifactorial, it is reasonable to hypothesize that age-related changes in androgens and other hormones might contribute to the development of MetS in older persons. However, this hypothesis has never been tested in older women. We hypothesized that high levels of testosterone, dehydroepiandrosterone sulfate (DHEA-S), and cortisol and low levels of sex hormone-binding globulin (SHBG) and IGF-I would be associated with MetS in a representative cohort of older Italian women independently of confounders (including inflammatory markers). After exclusion of participants on hormone replacement therapy and those with a history of bilateral oophorectomy, 512 women (≥65 yr) had complete data on testosterone, cortisol, DHEA-S, SHBG, fasting insulin, total and free IGF-I, IL-6, and C-reactive protein (CRP). MetS was defined according to ATP-III criteria. Insulin resistance was calculated according to HOMA. MetS was found in 145 women (28.3%). Participants with vs. those without MetS had higher age-adjusted levels of bioavailable testosterone (P < 0.001), IL-6 (P < 0.001), CRP (P < 0.001), and HOMA (P < 0.001) and lower levels of SHBG (P < 0.001). After adjustment for potential confounders, participants with decreased SHBG had an increased risk of MetS (P < 0.0001) vs. those with low SHBG. In a further model including all hormones and confounders, log SHBG was the only independent factor associated with MetS (OR: 0.44, 95% CI 0.21–0.91, P = 0.027). In older women, SHBG is negatively associated with MetS independently of confounders, including inflammatory markers and insulin resistance. Further studies are needed to support the notion that raising SHBG is a potential therapeutic target for prevention and treatment of MetS.
doi:10.1152/ajpendo.00339.2006
PMCID: PMC2645662  PMID: 16968811
sex hormone-binding globulin; hormonal dysregulation; insulin-like growth factor I; androgens
14.  Human sex hormone–binding globulin variants associated with hyperandrogenism and ovarian dysfunction 
The access of testosterone and estradiol to target tissues is regulated by sex hormone–binding globulin (SHBG) in human blood. Serum SHBG levels are low in patients with hyperandrogenism, especially in association with polycystic ovarian syndrome (PCOS) and in individuals at risk for diabetes and heart disease. Here, we identify SHBG coding region variations from a compound heterozygous patient who presented with severe hyperandrogenism during pregnancy. Serum SHBG levels in this patient measured 2 years after her pregnancy were exceptionally low, and her non–protein-bound testosterone concentrations greatly exceeded the normal reference range. A single-nucleotide polymorphism within the proband’s maternally derived SHBG allele encodes a missense mutation, P156L, which allows for normal steroid ligand binding but causes abnormal glycosylation and inefficient secretion of SHBG. This polymorphism was identified in four other patients with either PCOS, ioiopathic hirsutism, or ovarian failure. The proband’s paternal SHBG allele carries a single-nucleotide deletion within exon 8, producing a reading-frame shift within the codon for E326 and a premature termination codon. CHO cells transfected with a SHBG cDNA carrying this mutation fail to secrete the predicted truncated form of SHBG. To our knowledge, these are the first examples of human SHBG variants linked to hyperandrogenism and ovarian dysfunction.
doi:10.1172/JCI14060
PMCID: PMC150924  PMID: 11927624
15.  Associations of sex hormone-binding globulin and testosterone with diabetes among men and women (the Saku Diabetes study): a case control study 
Background
Sex hormone-binding globulin (SHBG) levels and sex hormones have been implicated in the pathogenesis of type 2 diabetes and cardiovascular diseases. As fatty liver has been suggested to be a major determinant of SHBG levels, we examined whether the associations of SHBG and testosterone with diabetes were independent of fatty liver.
Methods
We conducted a case–control study that included 300 diabetes cases (215 men and 85 women) and 300 matched controls from the Saku cohort study. Diabetes was defined by either fasting plasma glucose levels ≥126 mg/dL, 2-h post-load glucose levels ≥200 mg/dL after a 75 g oral glucose tolerance test, or diabetes diagnosed by physicians. We fitted conditional logistic regression models to examine the associations between SHBG and total testosterone levels with diabetes by sex. To evaluate the impact of fatty liver, we used the fatty liver index (FLI), a validated measure derived from serum triglyceride levels, body mass index (BMI), waist circumference, and γ-glutamyltransferase levels.
Results
After adjusting for age, family history of diabetes, smoking, physical activity, BMI, and FLI, SHBG levels were inversely associated with diabetes among women (odds ratio [OR] comparing the highest with the lowest quartiles, 0.13 [95% confidence interval {CI}, 0.02–0.96]), but not among men. Similar patterns were observed in a subgroup analysis restricted to postmenopausal women"(OR, 0.12 [95% CI, 0.01–1.17]). In contrast, testosterone levels were inversely associated with diabetes among men (OR, 0.45 [95% CI, 0.23–0.89]), but not among women.
Conclusions
Our findings suggest that SHBG in women and testosterone in men may be inversely associated with diabetes.
doi:10.1186/1475-2840-11-130
PMCID: PMC3537568  PMID: 23066943
Sex hormone; Sex hormone-binding globulin; Sex difference; Fatty liver disease
16.  Intra-Abdominal Adipose Tissue Is Independently Associated With Sex-Hormone Binding Globulin in Premenopausal Women 
Obesity (Silver Spring, Md.)  2012;20(5):1012-1015.
Lower serum concentrations of sex-hormone binding globulin (SHBG) are associated with increased risk for several obesity-related diseases in women including hormone-sensitive cancers, type 2 diabetes, metabolic syndrome, and cardiovascular disease. Previous investigations have reported that body composition, specifically central obesity, and/or higher insulin concentrations are key factors associated with lower SHBG in overweight and obese women; however, these studies were limited by their cross-sectional design. We hypothesized that intra-abdominal adipose tissue (IAAT), a fat depot linked with an abnormal metabolic profile, is inversely and independently associated with SHBG. Therefore, we determined the longitudinal associations among SHBG, insulin, and IAAT in 107 premenopausal women enrolled in a weight loss study. Overweight (BMI 27–30 kg/m2) women were weight reduced until BMI of ≤24 was achieved. Body composition and IAAT were measured at baseline and after weight loss with dual-energy X-ray absorptiometry and computed tomography, respectively. Serum concentrations of insulin and SHBG were determined. Paired t-test showed that insulin and IAAT decreased significantly and SHBG increased significantly following weight loss (P < 0.0001 for all). Simple correlations from baseline showed no association with insulin and SHBG (r = −0.142, P = 0.143) and a significant inverse association between IAAT and SHBG (r = −0.43, P < 0.0001). Repeated measures mixed-model showed that after adjusting for age and time (weight loss), IAAT was significantly inversely associated with SHBG (P = 0.0002) and there was no association with insulin and SHBG (P = 0.180). We conclude that SHBG concentrations are influenced by IAAT and not insulin in premenopausal women.
doi:10.1038/oby.2011.375
PMCID: PMC3626111  PMID: 22222925
17.  Interrelation Between Sex Hormones and Plasma Sex Hormone-Binding Globulin and Hemoglobin A1c in Healthy Postmenopausal Women 
Abstract
Background
Androgenicity, as measured by low sex hormone-binding globulin (SHBG) and elevations in testosterone and free androgen index (FAI), is associated with adverse cardiovascular (CV) outcomes, possibly due to effects on insulin resistance and glycemia.
Methods
Glycosylated hemoglobin (HbA1c) concentration, SHBG, and sex hormones were available in 200 non-diabetic postmenopausal women who were not using hormone therapy (HT) in the Women's Health Study. Of these, 98 were cardiovascular disease (CVD) cases; the remainders were matched controls. To achieve normality, continuous values were log transformed and geometric means were calculated. Associations between sex hormones and HbA1c were examined using general linear models (GLM), partial correlations, and multiple linear regression analyses.
Results
Lower SHBG levels and higher FAI and HbA1c values were found among the CVD cases, and all analyses were adjusted for this factor. In GLM, higher values of HbA1c were observed in the highest quartiles of FAI and the lowest quartiles of SHBG. However, the correlation between SHBG and HbA1c across quartiles was eliminated after adjusting for body mass index (BMI). In partial correlations, HbA1c values were inversely associated with SHBG (r = −0.19, P = 0.008) and positively associated with FAI (r = 0.19, P = 0.01), even after adjusting for age, CVD case–control status, and BMI. In multivariate models, a significant inverse association between SHBG and HbA1c persisted, as well as a significant positive association between FAI and HbA1c.
Conclusions
Androgenicity, as measured by low SHBG and high FAI, is associated with glycemia, and thereby may contribute to CVD risk in postmenopausal women.
doi:10.1089/met.2008.0081
PMCID: PMC2880893  PMID: 19344226
18.  Sex Hormone–Binding Globulin as an Independent Predictor of Incident Type 2 Diabetes Mellitus in Men 
Background.
Low levels of sex hormone–binding globulin (SHBG) and total testosterone (T) in men have been associated with increased risk of type 2 diabetes mellitus (T2DM). As total T and SHBG levels are highly correlated, we determined whether SHBG influences the risk of T2DM through T or whether SHBG is an independent predictor of T2DM.
Methods.
Longitudinal analyses were conducted on men participating in the Massachusetts Male Aging Study, a population-based study of men aged 40–70 years. Of 1,709 men enrolled in 1987–1989, 1,156 were evaluated 7–10 years later and 853 after 15–17 years. Analyses were restricted to 1,128 men without T2DM at baseline.
Results.
Ninety new cases of T2DM were identified. After adjustment for age, body mass index, hypertension, smoking, alcohol intake, and physical activity, the hazard ratio (HR) for incident T2DM was 2.0 for each 1 SD decrease in SHBG (95% confidence interval [CI], 1.42–2.82, p < .001) and 1.29 for each 1 SD decrease in total T (95% CI, 1.01–1.66, p = .04). Free T was not associated with T2DM (HR = 1.03, 95% CI, 0.81–1.31, p = .79). The strong association of T2DM risk with SHBG persisted even after additional adjustment for free T (HR = 2.04, 95% CI, 1.44–2.87, p < .0001) or total T (HR = 1.95, 95% CI, 1.34–2.82, p = .0004).
Conclusions.
SHBG is an independent predictor of incident T2DM even after adjusting for free T or total T. Free T is not significantly associated with T2DM. SHBG may contribute to the risk of T2DM through nonandrogenic mechanisms, which should be investigated as they may provide novel targets for diabetes prevention.
doi:10.1093/gerona/glq002
PMCID: PMC2854882  PMID: 20106959
SHBG; Type-2 diabetes; Testosterone
19.  The effects of caffeinated and decaffeinated coffee on sex hormone-binding globulin and endogenous sex hormone levels: a randomized controlled trial 
Nutrition Journal  2012;11:86.
Background
Findings from observational studies suggest that sex hormone-binding globulin (SHBG) and endogenous sex hormones may be mediators of the putative relation between coffee consumption and lower risk of type 2 diabetes. The objective of this study was to evaluate the effects of caffeinated and decaffeinated coffee on SHBG and sex hormone levels.
Findings
After a two-week run-in phase with caffeine abstention, we conducted an 8-week parallel-arm randomized controlled trial. Healthy adults (n = 42) were recruited from the Boston community who were regular coffee consumers, nonsmokers, and overweight. Participants were randomized to five 6-ounce cups of caffeinated or decaffeinated instant coffee or water (control group) per day consumed with each meal, mid-morning, and mid-afternoon. The main outcome measures were SHBG and sex hormones [i.e., testosterone, estradiol, dehydroepiandrosterone sulfate].
No significant differences were found between treatment groups for any of the studied outcomes at week 8. At 4 weeks, decaffeinated coffee was associated with a borderline significant increase in SHBG in women, but not in men. At week 4, we also observed several differences in hormone concentrations between the treatment groups. Among men, consumption of caffeinated coffee increased total testosterone and decreased total and free estradiol. Among women, decaffeinated coffee decreased total and free testosterone and caffeinated coffee decreased total testosterone.
Conclusions
Our data do not indicate a consistent effect of caffeinated coffee consumption on SHBG in men or women, however results should be interpreted with caution given the small sample size. This is the first randomized trial investigating the effects of caffeinated and decaffeinated coffee on SHBG and sex hormones and our findings necessitate further examination in a larger intervention trial.
doi:10.1186/1475-2891-11-86
PMCID: PMC3502342  PMID: 23078574
Coffee; Sex hormones; Randomized trial
20.  Sex Hormone-Binding Globulin and Type 2 Diabetes Mellitus 
Sex hormone-binding globulin (SHBG) has emerged as one of the multiple genetic and environmental factors that potentially contribute to the pathophysiology of Type 2 diabetes mellitus (T2DM). In addition to epidemiologic studies demonstrating a consistent relationship between decreased levels of serum SHBG and incident T2DM, recent genetic studies also reveal that transmission of specific polymorphisms in the SHBG gene influence risk of T2DM. On the molecular level, elucidation of the multiple interactions between SHBG and its receptors in various target tissues, suggest physiologic roles for SHBG that are more complex than the simple transport of sex hormones in serum. Taken together, these data provide support for an expanded role of SHBG in the pathophysiology of insulin resistance and T2DM.
doi:10.1016/j.tem.2011.09.005
PMCID: PMC3351377  PMID: 22047952
genetic polymorphisms; sex hormone binding globulin; type 2 diabetes mellitus
21.  Inverse association between serum insulin and sex hormone-binding globulin in a population survey in Sweden 
Endocrine Connections  2012;2(1):18-22.
Objectives
Obesity is associated with low levels of sex hormone-binding globulin (SHBG). While the reason is not fully understood, we aimed to study the association between serum insulin and levels of SHBG in a random population.
Design and methods
Between 2001 and 2005, a random sample of 2816 participants aged 30–74 years were enrolled in a cross-sectional survey in the South-west of Sweden. Fasting blood samples were collected and an oral glucose tolerance test (OGTT) was conducted in all subjects without known diabetes. Diabetes mellitus was defined according to criteria from WHO, and clinical characteristics were used to discriminate between type 1 (T1D) and type 2 diabetes (T2D). Analyses of SHBG were successful in 2782 participants (98%), who thus constituted the current study population.
Results
We found significant inverse association between levels of SHBG and fasting serum insulin in both genders (men: β=−0.090, P=0.001; women: β=−0.197, P<0.001), which was independent of differences in age and BMI. The associations remained when also differences in fasting plasma glucose were accounted for (men: β=−0.062, P=0.022; women: β=−0.176, P≤0.001). Subjects with T1D exhibited higher levels of SHBG than both T2D (men: δ=15.9 nmol/l, P<0.001; women: δ=71.1 nmol/l, P<0.001) and non-diabetic subjects (men: δ=15.1 nmol/l, P<0.001; women: δ=72.9 nmol/l, P<0.001) independent of age, BMI and fasting glucose levels.
Conclusion
These findings are consistent with high levels of SHBG in T1D, and correspondingly low levels in T2D subjects, suggesting an inhibitory effect of insulin on the SHBG production in the liver.
doi:10.1530/EC-12-0057
PMCID: PMC3680959  PMID: 23781314
sex hormone-binding globulin; insulin; liver; diabetes
22.  Sex hormone binding globulin, free estradiol index, and lipid profiles in girls with precocious puberty 
Purpose
Sex hormone-binding globulin (SHBG) modulates the availability of biologically active free sex hormones. The regulatory role of SHBG might be important in the relationship between hormone levels and the modification of lipid profiles in girls with precocious puberty. However, few studies have evaluated the relationship of SHBG, free estradiol index (FEI), and lipid levels in these girls.
Methods
One hundred and nine girls less than 8 years of age with pubertal development were enrolled. FEI was calculated with SHBG and estradiol (E2). We analyzed SHBG between peak luteinizing hormone (LH)≥5 (IU/L) (group 1) and LH<5 (IU/L) (group 2) through a gonadotropin releasing hormone stimulation test.
Results
Body mass index (BMI) standard deviation score (SDS) was higher in group 2 than in group 1 (P=0.004). Serum SHBG levels did not differ and FEI was not higher in group 1 (P=0.122). Serum cholesterol, HDL, and LDL did not differ; however, triglyceride levels were higher in group 2 (P=0.023). SHBG was negatively correlated with bone age advancement, BMI, BMI SDS, and FEI, and was positively correlated with HDL. However, SHBG was not correlated with E2 or peak LH.
Conclusion
Serum SHBG itself might not be associated with precocious puberty in girls, but it might be related to BMI and lipid profiles. Further studies are needed to reveal the relationship between sex hormone and obesity in girls with precocious puberty.
doi:10.6065/apem.2013.18.2.81
PMCID: PMC4027091  PMID: 24904857
Sex hormone-binding globulin; Estradiol; Lipid; Precocious puberty
23.  Sex Hormone Binding Globulin and Testosterone in Individuals with Childhood Diabetes 
Diabetes care  2008;31(6):1207-1213.
Objective
Insulin down-regulates hepatic production of sex hormone binding globulin (SHBG), which in turn influences sex hormone bioavailability. The effects of childhood-onset diabetes, and of insulin resistance in nondiabetics, on SHBG and testosterone in children and young adults are poorly understood.
Research Design and Methods
Individuals with diabetes diagnosed <18 years of age (n=48) and their siblings without diabetes (n=47) were recruited for the Chicago Childhood Diabetes Registry Family Study. SHBG and total and free testosterone were measured. Participants ranged in age from 10-32 years; 39% were Non-Hispanic white. The majority of individuals with diabetes were classical type 1 phenotype (75%), while the remainder exhibited features of type 2 or mixed diabetes; 96% were treated with insulin.
Results
SHBG and total testosterone were higher in males with diabetes compared to male siblings. Elevated SHBG was associated with the absence of endogenous insulin independent of gender; elevated total testosterone was similarly associated with the absence of C-peptide but only for males. Diabetes type and treatment were unrelated. In those without diabetes, greater insulin resistance had a small, nonsignificant association with lower SHBG and higher free testosterone.
Conclusions
SHBG and total testosterone appear to be higher in male children and young adults with diabetes compared to nondiabetic male siblings, apparently related to the absence of endogenous insulin. This may have implications for sex hormone-dependent processes across the lifespan in males diagnosed with diabetes as children.
doi:10.2337/dc07-2169
PMCID: PMC2493542  PMID: 18346991
sex hormone binding globulin; testosterone; C-peptide; insulin resistance
24.  Liver fat and SHBG affect insulin resistance in midlife women: The Study of Women’s Health Across the Nation (SWAN) 
Obesity (Silver Spring, Md.)  2013;21(5):1031-1038.
The liver is an insulin-responsive organ that contributes significantly to both whole body insulin sensitivity and availability of sex steroids through the production of sex hormone binding globulin (SHBG). Our objective was to explore whether lower SHBG was associated with ectopic liver fat and mediated its effect on insulin resistance in The Study of Women’s Health Across the Nation (SWAN). A subset of midlife African American and Caucasian women from SWAN (n=208; 50.9±0.18 yrs; 71% Caucasian) had computed tomography scans to quantify visceral, subcutaneous and liver fat. Blood samples were collected and assayed for hormonal and metabolic markers. The cohort, while overweight, was generally healthy, and both liver fat and SHBG were unaffected by menopausal stage or race. Both higher liver fat and lower SHBG levels were significantly associated with higher insulin concentrations after adjustment for adiposity (r=−0.25, p<0.001 and r=−0.18, p=0.01). SHBG and liver fat had additive effects on insulin concentrations such that women with the lowest SHBG and the highest fat levels had the highest values (interaction p=0.09). The association between SHBG and insulin was more apparent among women with fattier livers. SHBG and liver fat appear to have independent effects on insulin levels as adjustment for each other did not diminish the strength of either association (p=0.023 and 0.001 respectively). These results confirmed the strong independent associations between increased liver fat and decreased SHBG with increased metabolic risk in midlife women. Further these data underscore the need for additional research into the role of liver fat in modifying SHBG’s influence on insulin levels.
doi:10.1002/oby.20077
PMCID: PMC3695405  PMID: 23784907
liver fat; sex hormone binding globulin; perimenopause; ectopic fat; insulin resistance
25.  Interrelation between Sex Hormones and Plasma Sex Hormone–Binding Globulin and Hemoglobin A1c in healthy postmenopausal women 
Background
Androgenicity, as measured by low sex hormone-binding globulin (SHBG) and elevations in testosterone and free androgen index (FAI), is associated with adverse cardiovascular (CV) outcomes, possibly due to effects on insulin resistance and glycemia.
Methods
Glycosylated hemoglobin (HbA1c) concentration, total testosterone, estradiol, SHBG, FAI, free estrogen index (FEI), and HbA1c were available in 200 nondiabetic postmenopausal women who were not using hormone therapy (HT) in the Women's Health Study. Of these, 98 were CVD cardiovascular disease (CVD) cases, while the remainders were matched controls. To achieve normality, continuous values were log transformed and geometric means were calculated. Associations between sex hormones and HbA1c were examined using general linear models (GLM), partial correlations and multiple linear regression analyses.
Results
Lower SHBG levels and higher FAI and HbA1c values were found among women who were CVD cardiovascular disease (CVD) cases compared to controls, and all analyses were adjusted for this factor. In GLM, higher values of HbA1c were observed in the highest quartiles of FAI and the lowest quartiles of SHBG. However, the correlation between SHBG and HbA1c across quartiles was eliminated after adjusting for body mass index (BMI). In partial correlations, HbA1c values were inversely associated with SHBG (r=-0.19, p=0.008) and positively associated with FAI (r=0.19, p=0.01), even after adjusting for age, CVD case-control status and BMI. In multivariable linear models, a significant inverse association between SHBG and HbA1c persisted, as well as, a significant positive association between FAI and HbA1c.
Conclusions
Androgenicity, as measured by low SHBG and high FAI, is associated with glycemia, and thereby may contribute to CVD risk in post-menopausal women.
doi:10.1089/met.2008.0081
PMCID: PMC2880893  PMID: 19344226
sex hormones; hemoglobin A1c; postmenopausal women

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