Sex Hormone-binding Globulin Gene Polymorphism Research Articles

SHBG gene polymorphisms and their influence on serum SHBG, total and free testosterone concentrations in men.

Genetic variation in sex hormone-binding globulin (SHBG) structure may affect estimates of sex steroid exposure by altering the affinity of the protein for its ligand. Consequently, free hormone calculations assuming constant binding affinity may, for certain genetic variations, lead to incorrect diagnoses if genetic variation is not taken into consideration. To investigate the effects of genetic variation in SHBG on calculated and measured serum free testosterone (T) in men. Population-based sibling-pair study in 999 healthy men aged 25 to 45 (mean: 34.5) years. Genotyping using microarray (Illumina®) for SNPs suggested to affect binding affinity and/or concentration of SHBG or T. SHBG concentrations were measured using immunoassay and in a subset (n = 32) by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Total T was measured using LC-MS/MS. Free T was calculated and in a subset (n = 314) measured directly using LC-MS/MS after equilibrium dialysis. Allelic frequencies of analyzed SNPs ranged from 0.5% to 58.2%. Compared to wild-type, SHBG concentrations were lower in rs6258 heterozygotes (-24.7%; p < 0.05) and higher in rs6259 heterozygotes, rs727428 homozygotes, and carriers of rs1799941 (+10.8 to 23.1%; all p < 0.05). Total T was higher in rs727428 homozygotes and carriers of rs5934505, rs1799941and rs6259 (+3.9 to 21.4%; all p < 0.05). No clear effects on measured free T were found, except for a trend towards higher values in rs6259 homozygotes, significant for calculated free T (+18.7%; p < 0.05) in the larger global study population. In these men, analyzed SNPs were relatively prevalent and affected serum concentrations of total T and SHBG but not calculated or measured free T except for a higher trend in rs6259 homozygotes.

Association of sex hormone-binding globulin gene polymorphism and sex hormone-binding globulin levels in postmenopausal women in relation to type 2 diabetes mellitus – A case–Control study

Association of sex hormone-binding globulin gene polymorphism and sex hormone-binding globulin levels in postmenopausal women in relation to type 2 diabetes mellitus – A case–Control study

Effect of Sex Hormone-Binding Globulin on Polycystic Ovary Syndrome: Mechanisms, Manifestations, Genetics, and Treatment.

Polycystic ovary syndrome (PCOS) is one of the most common endocrine diseases causing infertility in women of childbearing age. It is characterized by hyperandrogenemia (HA), chronic anovulation, and polycystic ovary morphology (PCOM). Most women with PCOS have metabolic abnormalities. Sex hormone-binding globulin (SHBG), a transport carrier that binds estrogen and androgens and regulates their biological activity, is usually used as an indicator of hyperandrogenism in women with PCOS. Low serum SHBG levels are considered a biomarker of metabolic abnormalities and are associated with insulin resistance (IR), HA, and abnormal glucose and lipid metabolism in PCOS patients. SHBG is also related to the long-term prognosis of PCOS, whereas SHBG gene polymorphism is associated with PCOS risk. In addition, the administration of metformin (MET), glucagon-like peptide-1 receptor agonists (GLP-1 RAs), thiazolidinediones (TZDs), compound oral contraceptives (COCs), as well as nutrient supplements such as inositol (MI), vitamin D, and synbiotics can regulate SHBG levels to ameliorate PCOS complications and improve prognosis. This review focuses on the interaction between SHBG and various PCOS complications as well as the regulation of SHBG by various drugs and nutrients and its therapeutic effects on PCOS.

The effect of sex hormone-binding globulin gene polymorphisms on the serum level of SHBG hormone in the men with prostate cancer

To evaluated the possible correlations of prostate cancer and three coding region polymorphisms (rs 6257, rs6258, rs 6259), & changing repeat of TAAAA in promoter of SHBG gene regarding to concentration of Prostate specific Antigen and SHBG levels. For study purpose, a total of 352 subjects (176 patients and 176 controls) were recruited. The ELISA technique and the RFLP-PCR method were used. Logistic and adjusted regression of genotypes showed that the (TAAAA)n polymorphism in individuals carrying more than five repeats of the five-nucleotide sequence of TAAAA, as well as AA+AG (rs6257) and AA+AG (rs6259), increased the risk of prostate cancer by the chance ratio of 1.622, 2.005, and 2.469, respectively. The studied polymorphisms showed a significant relationship with the stage of the disease and Gleason score. The individuals carrying the mutants were less likely to develop prostate cancer than the ones with wild genotypes. All the genotypes in the cancer group had higher serum levels of tPSA and fPSA than those in the control group. A significant association was observed (except tPSA and fPSA for GT (rs6258) and fPSA for GA (rs6259)). Serum level of SHBG also showed a significant correlation with prostate cancer in genotypes >Panta TAAAA (TAAAA)n, GG (rs6257), TT and TT + CT (rs6258), and GG, AA, and AA+GA (rs6259). These polymorphisms by changing the serum levels SHBG contributed to the incidence of prostate cancer.

Genetic Polymorphism in Sex Hormone-binding Globulin With a Prognosis of Androgen Deprivation Therapy in Metastatic Prostate Cancer Among Japanese Men.

Testosterone suppression in serum during androgen deprivation therapy (ADT) can affect the oncologic outcome of ADT. Although genetic variants in sex hormone-binding globulin (SHBG) were reported to be correlated with serum testosterone level, the association with serum testosterone during ADT remains unclear. Therefore, this study investigated the impact of a missense polymorphism in the SHBG gene among men treated with primary ADT for metastatic prostate cancer. This study included 104 Japanese men with metastatic prostate cancer. The association of SHBG gene polymorphism (rs6259, D356N) with clinicopathologic parameters including serum testosterone levels during ADT, as well as prognosis, including progression-free survival and overall survival, was examined. The serum testosterone levels during ADT were comparable between men carrying the homozygous wild-type (GG) and heterozygous/homozygous variant (GA/AA) in the SHBG gene. When adjusted for age, Gleason score, initial prostate-specific antigen, and clinical T-stage, the heterozygous/homozygous variant (GA/AA) in the SHBG gene was associated with a higher risk of progression (hazard ratio, 2.20; 95% confidence interval, 1.10-4.18; P= .027) and any-cause death (hazard ratio, 3.21; 95% confidence interval, 1.31-7.35; P= .012). This study suggested genetic variation in SHBG (rs6259) might be an independent prognostic biomarker among men treated with primary ADT for metastatic prostate cancer.

Testosterone levels and the genetic variation of sex hormone-binding globulin gene of Bubalus bubalis, bulls in Egypt

Testosterone is themain plasma androgen produced and secreted by male testis. To be bioactive, it binds to sex hormonebinding globulin (SHBG), i.e. the major transporter protein of sex steroids in the blood of mammals and other vertebrate species.Firstly, this study aimed to determine the levels of testosterone in different-age groups of buffalo bulls (Bubalus bubalis) in Egypt, and secondly to screen the genetic polymorphisms in their SHBG gene and to investigatewhether these polymorphisms are associated with the level of the circulating serum testosterone. Blood samples were collected from 67 Egyptian buffalo bulls representing four different age-groups and testosterone concentration was measured by radioimmunoassay. Selected DNA samples from different age-groups were sequenced for the full length of theirSHBGgene.Asignificant increase in the concentration of serum testosterone in buffalo bulls was recorded with the advancement of age from 12/18 to 24/36 months. Based on the number of polymorphisms in SHBG gene, the current study reveals the presence of three bull genotypes, of which one is likely to be associated with low testosterone concentration, while other is likely to be associated with an increased testosterone concentration. Such genetic associations can provide a good tool for the selection of bull genotypes with higher testosterone concentrations, which are indispensible for breeding purposes.

Correlation between SHBG gene polymorphism and male infertility in Han population of Henan province of China: A STROBE-compliant article.

Human sex hormone binding globulin (SHBG) level alteration and SHBG gene mutations, especially in rs6259 and rs727428 loci, are associated with male infertility. In this study, the rs6259 and rs727428 loci in SHBG gene were detected by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) to explore the direct relation between these 2 loci and male infertility in Han population of Henan province and to provide information for the pathogenesis, diagnosis, and treatment of male infertility.A total of 366 male Han individuals in Henan province were enrolled in this study. Of the 366 male individuals, 183 infertility patients were served as infertility group and other 183 normal individuals as a control group. SHBG gene rs6259 and rs727428 locus polymorphisms were detected by PCR-RFLP in all patients. Also, genotype frequencies, allele frequency, and haplotype were all analyzed in both groups.There were statistical differences in A allele frequency (P = .017) and GA genotype frequency (P = .016) of SHBG gene rs6259 locus and in CC genotype frequency of SHBG gene rs727428 locus (P = .034) between the 2 groups.Male infertility is associated with GA genotype and A allele of rs6259 locus, as well as CC genotype of rs727428 locus in SHBG gene.

The association between sex hormone-binding globulin gene polymorphism with bone mineral density

To investigate the impact of single nucleotide polymorphisms (SNPs) of SHBG gene the neighboring genes on SHBG levels, bone mineral density (BMD) and osteoporosis in Chinese males. A group of Chinese men, aged ⩾45years were included in the analysis. BMD was measured with dual-energy X-ray absorptiometry (DXA), SHBG and total testosterone (TT) was measured using chemiluminescent immunoassay, and free testosterone (FT) was calculated. SNPs of SHBG gene and the neighboring genes were studied by means of improved multiple ligase detection reaction (iMLDR). A total of 404 men were included in our study. In the single locus analysis, significant associations were found between SHBG levels and four polymorphisms (rs11078701, rs9901675, rs9898876 and rs2541012) in age- and BMI-adjusted models. In addition, statistically significant difference was found between osteoporosis patients and control subjects in genotype distributions of rs9898876, rs2541012, rs6259 and rs3853894. In the models with or without adjustment for confounders (age, BMI, SHBG and free testosterone (FT) levels), carriers of variant genotype of rs9898876, rs2541012 and rs6259 had lower BMD and were more likely to suffer from osteoporosis, as compare to carriers of common genotype. Subjects with variant genotype of rs3853894 had higher BMD and were less likely to suffer from osteoporosis, as compared to subjects with common genotype. In the haplotypes analysis, CCGGT (constituted by rs11078701C, rs1017163C, rs9898876G, rs62059836G and rs2541012T) and haplotype CGGT (constituted by rs858521C, rs858518G, rs6259G and rs727428T) was associated with a significant risk effect for osteoporosis. Polymorphisms of SHBG or the neighboring genes were associated with SHBG levels or BMD and osteoporosis, suggesting the involvement of genetic variation of SHBG in bone health.

Study of Sex Hormone-binding Globulin Gene Polymorphism and Risk of Type 2 Diabetes Mellitus in Egyptian Men.

Conditions of hypoandrogenism in men have been linked to insulin resistance, suggesting that alterations in normal sex steroid physiology could play a role in the pathogenesis of Type 2 diabetes mellitus (T2DM). Sex hormone-binding globulin (SHBG) gene polymorphisms may be the cause of sex steroid alteration. The aim of this work is to study the effect of SHBG gene polymorphisms on the risk of T2DM through its impact on testosterone and oestradiol level in Egyptian men. A case control study was performed in the diabetes clinic at Zagazig University Hospital on 185 males with Type 2 diabetes and their matched healthy controls. Two polymorphisms (rs6257 and rs6259) of the gene encoding SHBG were genotyped and serum levels of SHBG, testosterone and oestradiol were measured by enzyme-linked immunosorbent assay (ELISA). Carriers of rs6257 variant allele (CC or CT) and carriers of rs6259 wild allele (GG) appear to have a high risk of diabetes than carriers of other alleles (OR 2.241, 1.585 and 2.391, respectively). They also showed a significant decrease in plasma level of both SHBG and testosterone and a significant increase in oestradiol blood level compared with carriers of other alleles. Sex hormone-binding globulin gene polymorphisms at position rs6257 and rs6259 are associated with higher risk of T2DM in Egyptian men, through lowering circulating levels of SHBG and consequently, lowering testosterone and elevating oestradiol level.

SHBG Gene Polymorphism (rs1799941) Associates with Metabolic Syndrome in Children and Adolescents

BackgroundMetabolic syndrome (MetS) is a complex disorder characterized by coexistence of several cardiometabolic (CM) factors, i.e. hyperlipidemia, obesity, high blood pressure and insulin resistance. The presence of MetS is strongly associated with increased risk of cardiovascular disease (CVD). The syndrome was originally defined as an adult disorder, but MetS has become increasingly recognized in children and adolescents.MethodsGenetic variants influence biological components common to the CM factors that comprise MetS. We investigated single locus associations between six single nucleotide polymorphisms (SNPs), previously shown to modulate lipid or sex hormone binding globulin (SHBG) levels, with MetS in a Turkish pediatric cohort (37 cases, 323 controls).ResultsLogistic regression analysis revealed a significant association between rs1799941, located in SHBG, and MetS (OR = 3.09, p-value = 0.006). The association with MetS remained after sequential adjustment for each CM factor included in the syndrome definition, indicating that the identified association is not being driven by any single trait. A relationship between rs1799941 and SHBG levels, was also discovered, but it was dependent on MetS status. In control subjects, the A allele of rs1799941 associated with a significant increase in SHBG levels (p = 0.012), while in cases there was no association between rs1799941 and SHBG levels (p = 0.963).ConclusionsThe significant association between rs1799941 and MetS in children is not contingent on any single CM trait. Additionally, the presence of MetS may abrogate effect of rs1799941 polymorphism on SHBG levels in children.

SEX HORMONE BINDING GLOBULIN GENE POLYMORPHISM AND RISK OF TYPE2 DIABETES MELLITUS IN EGYPTIAN MEN

Conditions of hypoandrogenism in men have been linked to insulin resistance, suggesting that alterations in normal sex steroid physiology could play a role in the pathogenesis of type 2 diabetes (T2DM). Sex hormone binding globulin gene polymorphisms may be the cause of sex steroid alteration The aim of this work to study effect of sex hormone binding globulin (SHBG) gene polymorphisms on type 2 diabetes mellitus risk through its impact on testosterone and estradiol level in Egyptian men. In 185 diabetic men and 120 matched healthy controls, two polymorphisms (rs6257 and rs6259) of the gene encoding sex hormone–binding globulin were genotyped and serum levels of sex hormone–binding globulin, testosterone and estradiol were measured by ELISA; Our results showed significant decrease in sex hormone binding globulins in type 2 diabetic patients compared with the control group. Carrier of variant allele of SHBG single nucleotide polymorphism (SNP) rs6259 had a higher level of SHBG in serum (p=0.000) While carrier of SHBG rs6257 SNP had a lower level of SHBG level in serum SHBG gene polymorphisms are associated with risk of type 2 diabetes in Egyptian men, through lowering circulating levels of sex hormone–binding globulin and consequently lowering testosterone and elevating estradiol level. SHBG rs6257 genotype may have a predictive value of developing type II diabetes mellitus Key words: Diabetes mellitus, SHBG, gene polymorphism, testosterone, and estradiol.

Sex hormone binding globulin gene polymorphisms and metabolic syndrome in postmenopausal Turkish women

Insulin resistance is associated with obesity, glucose intolerance or diabetes, hypertension, dyslipidemia, and cardiovascular disease. Constellation of these risk factors iscalled metabolic syndrome (MetS). MetS is common among postmenopausal women. Low sex hormone binding globulin (SHBG) levels associate with an increased risk of MetS in postmenopausal women. Variations in SHBG gene associate with low levels of circulating SHBG levels. We aim to study the association between SHBG gene polymorphisms - rs1799941 (A/G) and rs6257 (T/C) - with MetS among postmenopausal women. The study population consisted of 182 postmenopausal women with MetS and 119 control subjects. We analyzed the allele frequencies of SHBG gene polymorphisms in relation to the risk components of MetS. MetS patients displayed significantly lower SHBG levels compared to the lean control subjects (p = 0.036). rs1799941 A allele was associated with high SHBG levels (p = 0.031), low blood pressure, body mass index and waist circumference. The number of 'high risk' alleles (G allele of the rs1799941 and T allele of rs6257) correlated positively with waist circumference (r = 0.203, p = 0.006) and negatively with SHBG levels (r = -0.291, p = 0.024). SHBG gene polymorphisms associate with SHBG levels and MetS risk components among postmenopausal women. Hence, A allele (rs1799941) may have a protective effect for MetS through its association with high SHBG levels among postmenopausal women.

Association of anthropometric, androgenic and insulin-related features with polymorphisms in exon 8 of SHBG gene in women with polycystic ovary syndrome

ABSTRACTObjective: Sex hormone binding globulin (SHBG) levels are often low in women with polycystic ovary syndrome (PCOS). In addition to metabolic and nutritional factors, SHBG levels are determined by genetic polymorphisms in SHBG gene. The aim of this study was to investigate the association of polymorphisms in exon 8 of SHBG gene with anthropometric and biochemical features of women with PCOS.Design: Prospective, observational study.Patients: One hundred and ninety-four women with PCOS.Main outcome measure(s): Genotype analysis of exon 8 in SHBG gene was performed. Serum SHBG, total testosterone, free testosterone, 17-α-hydroxyprogesterone, TSH, PRL, glucose and insulin levels were determined.Main finding(s): Single nucleotide polymorphism (SNP) E326K located at codon 326 in exon 8 of SHBG gene was identified. Serum SHBG levels decreased significantly with increasing copy number of the variant allele for SNP E326K after adjustment for BMI, androgenic and insulin-related traits. Genotype analysis also revealed SNP, rs6259, located at codon 327 in exon 8 of SHBG gene, which is not associated with SHBG levels.Conclusion: SNP, E326K, in exon 8 of SHBG gene may influence the metabolism of SHBG independently of BMI, androgenic and insulin-related features in women with PCOS.

Association of the (TAAAA) n repeat and Asp327Asn polymorphisms in the sex hormone-binding globulin (SHBG) gene with idiopathic male infertility and relation to serum SHBG concentrations

Sex hormone binding globulin (SHBG) is involved in delivering sex hormones to target tissues. We investigated the association between the (TAAAA) n repeat polymorphism, and Asp327Asn polymorphism in the SHBG gene with semen quality and idiopathic male infertility. We studied 168 men with idiopathic infertility [oligoasthenoteratozoospermia (OAT)] and equal number of age-matched normal controls. The serum levels of SHBG, reproductive and thyroid hormones, and Inhibin B were measured. Semen parameters were also assessed. The genotype assays for the SHBG polymorphism were done using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique. Baseline SHBG levels tended to be lower in infertile men (21.1 ± 7.2 nmol/l) compared to normal fertile men (24.7 ± 7.9 nmol/l). SHBG levels tended to be higher among the subjects with the Asn/Asn (25.84 ± 3.6 nmol/l) and S/S (24.50 ± 5.4 nmol/l) genotypes compared to subjects with the Asp/Asn (24.38 ± 3.2 nmol/l) and L/L (18.44 ± 4.2 nmol/l) genotypes of the SHBG gene. The genotype frequencies of Asp/Asp were 80.9% in cases and 71.4% in controls ( P = 0.001). The variant Asp/Asn genotype was associated with a more than 50% reduced risk of infertility (OR: 0.46, 95% CI: 0.25–0.80, P = 0.001). Genotype analysis demonstrated six SHBG (TAAAA) n alleles with 6–11 repeats. Long SHBG (TAAAA) n alleles (>8 repeats) were at greater frequency in infertile men than fertile subjects ( P = 0.001), whereas short SHBG (TAAAA) n alleles (≤8 repeats) tended to be more frequent in fertile men than cases ( P = 0.001). Men with the 9/X TAAAA repeat genotype displayed a 2.82-fold increased risk of infertility (95% CI: 1.27–4.79, P = 0.01). There were strong and significant positive correlations between plasma SHBG and sperm count ( r = 0.672, P = 0.01), sperm motility ( r = 0.721, P = 0.01) and sperm morphology ( r = 0.574, P = 0.02). We concluded that the SHBG Asp237Asn and (TAAAA) n polymorphisms may influence SHBG levels and as a result, male infertility. Multicenter large scale studies are warranted to better elucidate the role of SHBG gene polymorphism in male infertility.

Role of D327N sex hormone-binding globulin gene polymorphism in the pathogenesis of polycystic ovary syndrome

SHBG (sex hormone-binding globulin) is a transport protein specific for dihydrotestosterone, testosterone and estradiol. The missense mutation in exon 8 (GAC → AAC) causing the amino acid exchange Asp → Asn in codon 327 (D327N) correlates according to the published data with increased SHBG levels. We studied possible association of this polymorphism with polycystic ovary syndrome (PCOS) and anthropometric and biochemical parameters in 248 PCOS patients and 109 healthy control women. The D327N polymorphism (wild-type and variant allele) was detected using PCR-RFLP method (restriction enzyme Bbs-I). For statistical evaluation χ 2 test, Mann–Whitney test, ANCOVA, ANOVA (NCSS 2004, Statgraphics Plus v.5.1, USA) were used. There was no significant difference in genotype distribution between PCOS and controls ( χ 2 = 1.03, p = 0.59). Moreover, we did not find an association of the variant allele with plasma SHBG level, steroid hormones, or screened parameters of lipid and glucose metabolism. In conclusion, the D327N polymorphism of the SHBG gene does not influence susceptibility to PCOS.

The (TAAAA)n microsatellite polymorphism in the SHBG gene influences serum SHBG levels in women with polycystic ovary syndrome

Hyperandrogenaemia is a common feature of polycystic ovary syndrome (PCOS). The sex hormone-binding globulin (SHBG) gene was proposed as being a PCOS candidate gene. A possible influence of the microsatellite polymorphism (TAAAA)(n) in the SHBG gene on serum SHBG levels in PCOS patients was investigated. One hundred and twenty-three PCOS patients and 110 age-matched controls were included in the study. Peripheral blood samples were obtained. Genotyping of the (TAAAA)(n) polymorphism in the SHBG gene was performed. Serum LH, FSH, SHBG and total testosterone concentrations were determined. SHBG alleles with 6-11 TAAAA repeats were found. None of the SHBG alleles or genotypes were present at a significantly more frequent rate in PCOS patients compared with controls. Serum SHBG levels were significantly lower (P < 0.001) in PCOS patients compared with controls and were found to be strongly influenced by the (TAAAA)(n) SHBG polymorphism, in both the PCOS (55.3%) and control (33.1%) groups of patients. The (TAAAA)(n) SHBG gene polymorphism might be an important predictor for serum SHBG levels and, consequently, for hyperandrogenaemic clinical presentation of PCOS.

Association of SHBG gene polymorphism with menarche

The age of menarche may be subject to hereditary influences but the specific determinants are unknown. Our aim was to investigate the possible association of a functional (TAAAA)n polymorphism in the promoter of the sex hormone-binding globulin (SHBG) gene with the timing of menarche. This polymorphism has been associated with polycystic ovary syndrome (PCOS) and is considered to contribute to SHBG levels. We studied 130 healthy normal-weight adolescent females from a closed community in North-Western Greece. Information on menarche was obtained through interviews. The BMI was recorded. Genomic DNA was isolated from peripheral blood leukocytes for genotyping the TAAAA repeat region. We subdivided our subjects into two groups based on median age of menarche: those with menarche <13 years and those with menarche > or =13 years. Genotype analysis revealed six (TAAAA)n alleles containing 5-10 TAAAA repeats. The distribution of alleles was different in the two groups. Girls with late menarche had more frequently longer TAAAA alleles (>8 repeats), while girls with early menarche had shorter alleles at a greater frequency (P=0.048). The major contribution to early menarche was by the 6 TAAAA repeat allele. Furthermore, carriers of the longer allele genotypes had later menarche (13.24+/-1.15 years) than those with shorter allele genotypes (12.67+/-1.15, P=0.018). These findings provide evidence for a genetic contribution of SHBG gene to the age of menarche.