Erratum: An independent validation study of three single nucleotide polymorphisms at the sex hormone-binding globulin locus for testosterone levels identified by genome-wide association studies.
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SUBMITTER: Sato Y
PROVIDER: S-EPMC6276685 | biostudies-literature | 2017
REPOSITORIES: biostudies-literature
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Erratum: An independent validation study of three single nucleotide polymorphisms at the sex hormone-binding globulin locus for testosterone levels identified by genome-wide association studies.
Sato Youichi Y Tajima Atsushi A Katsurayama Motoki M Nozawa Shiari S Yoshiike Miki M Koh Eitetsue E Kanaya Jiro J Namiki Mikio M Matsumiya Kiyomi K Tsujimura Akira A Komatsu Kiyoshi K Itoh Naoki N Eguchi Jiro J Imoto Issei I Yamauchi Aiko A Iwamoto Teruaki T
Human reproduction open 20170614 1
[This corrects the article DOI: 10.1093/hropen/hox002.][This corrects the article DOI: 10.1093/hropen/hox002.]. ...[more]
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Project description:Study question:Are the single nucleotide polymorphisms (SNPs) rs2075230, rs6259 and rs727428 at the sex hormone-binding globulin (SHBG) locus, which were identified by genome-wide association studies (GWASs) for testosterone levels, associated with testosterone levels in Japanese men? Summary answer:The SNP rs2075230, but not rs6259 and rs727428, is significantly associated with testosterone levels in Japanese men. What is already known:Previous GWASs have revealed that rs2075230 is associated with serum testosterone levels in 3495 Chinese men and rs6259 and rs727428 are associated with serum testosterone levels in 3225 men of European ancestry. Study design size and duration:This is an independent validation study of 1687 Japanese men (901 in Cohort 1 and 786 in Cohort 2). Participants/materials setting and method:Cohort 1 (20.7 ± 1.7 years old, mean ± SD) and Cohort 2 (31.2 ± 4.8 years) included samples obtained from university students and partners of pregnant women, respectively. The three SNPs were genotyped using either TaqMan probes or restriction fragment length polymorphism PCR. Blood samples were drawn from the cubital vein of the study participants in the morning, and total testosterone and SHBG levels were measured using a time-resolved immunofluorometric assay. Association between each SNP and testosterone levels was evaluated by meta-analysis of the two Japanese male cohorts. Main results and the role of chance:The age of the two cohorts was significantly different (P < 0.0001). We found that rs2075230 was significantly associated with serum testosterone levels (? STD = 0.15, P = 7.2 × 10-6); however, rs6259 and rs727428 were not (? STD = 0.17, P = 0.071; ? STD = 0.082, P = 0.017, respectively), after adjusting for multiple testing in a combined analysis of two Japanese male cohorts. Moreover, rs2075230, rs6259 and rs727428 were significantly associated with high SHBG levels (? STD = 0.22, P = 3.4 × 10-12; ? STD = 0.23, P = 6.5 × 10-6 and ? STD = 0.21, P = 3.4 × 10-10, respectively). Large scale data:Not applicable. Limitations reasons for caution:This study had differences in the age and background parameters of participants compared to those observed in previous GWASs. In addition, the average age of participants in the two cohorts in our study also differed from one another. Therefore, the average testosterone levels, which decrease with age, between studies or the two cohorts were different. Wider implications of the findings:The three SNPs have a considerable effect on SHBG levels and hence may indirectly affect testosterone levels. Study funding/competing interests:This study was supported partly by the Ministry of Health and Welfare of Japan (1013201) (to T.I.), Grant-in-Aids for Scientific Research (C) (26462461) (to Y.S.) and (23510242) (to A.Ta.) from the Japan Society for the Promotion of Science, the European Union (BMH4-CT96-0314) (to T.I.) and the Takeda Science Foundation (to A.Ta.). There are no conflicts of interest to declare.
| S-EPMC6276698 | biostudies-literature
Project description:OBJECTIVE:The association ns between prediabetes and androgens have been rarely reported, especially in Chinese men. We aimed to investigate whether androgens were associated with the prevalence of prediabetes diagnosed with new American Diabetes Association criteria in Chinese men and then to assess which androgen value was the most relevant factor. METHODS:A total of 2654 men (52.6±13.4 years old) were selected. Serum total testosterone (TT), sex hormone-binding globulin (SHBG) and free testosterone (FT) were measured. Covariance analysis of different androgen values were performed in age subgroups. Multinomial logistic regression was used for the association of TT, SHBG and FT with prediabetes and diabetes, as well as prediabetes in age subgroups. RESULTS:According to ADA new criteria, normoglycemia, prediabetes, and diabetes were diagnosed in 1405, 907 and 342 men, respectively. In covariance analysis, SHBG of prediabetes were found lower than that of normoglycemia but higher than that of diabetes (P <0.05). In multinomial logistic regression, serum TT and SHBG were inversely associated with prediabetes and diabetes. While, after full adjustment for age, residence area, economic status, waist circumference, metabolic factors, other two androgen values and HOMA-IR, only the associations of SHBG with prevalence of prediabetes and diabetes persisted statistically significant, especially in the elderly with prediabetes (all P for trend <0.05). CONCLUSIONS:Serum androgen was inversely associated with prediabetes and diabetes in Chinese men. Low serum SHBG was the most relevant factor for prediabetes and diabetes. Whether it is an independent predictor for incident prediabetes in Chinese men needs further explorations.
| S-EPMC5008813 | biostudies-literature
Project description:Testosterone (T), sex hormone binding globulin (SHBG), free testosterone (FT) and bioavailable testosterone (BAT) are commonly employed tests in pediatric endocrinology and all require age-dependent reference intervals for interpretation. The common methods used to derive these reference intervals require decisions about data shape and/or age partition thresholds, which can result in sharp differences between age groups, particularly for pubescent children. Partitioning also results in a form of data loss, where data from one age-bin is completed disconnected from the adjacent age-bins. Non-parametric continuous reference intervals methods have previously been developed to avoid some of these drawbacks. These strategies use all the available data and smooth transitions between ages avoiding partitioning. However, the fitting process involves selection and adjustment of many parameters and it can be difficult to maintain a reproducible approach. Here we provide a workflow for non-parametric continuous reference intervals applied to T, FT, BAT, and SHBG using the R language quantregGrowth package. T measurements were determined by LC-MS/MS, FT and BAT were calculated, and SHBG was measured on the Roche Cobas e601. The continuous interval methodology is described in detail with code examples and illustrations for reproducibility.
| S-EPMC8662326 | biostudies-literature
Project description:Sex Hormone Binding Globulin (SHBG) is the major serum carrier of sex hormones. However, growing evidence suggests that SHBG is internalised and plays a role in regulating intracellular hormone action. This study was to determine whether SHBG plays a role in testosterone uptake, metabolism, and action in the androgen sensitive LNCaP prostate cancer cell line. Internalisation of SHBG and testosterone, the effects of SHBG on testosterone uptake, metabolism, regulation of androgen responsive genes, and cell growth were assessed. LNCaP cells internalised SHBG by a testosterone independent process. Testosterone was rapidly taken up and effluxed as testosterone-glucuronide; however this effect was reduced by the presence of SHBG. Addition of SHBG, rather than reducing testosterone bioavailability, further increased testosterone-induced expression of prostate specific antigen and enhanced testosterone-induced reduction of androgen receptor mRNA expression. Following 38 hours of testosterone treatment cell morphology changed and growth declined; however, cotreatment with SHBG abrogated these inhibitory effects. These findings clearly demonstrate that internalised SHBG plays an important regulatory and intracellular role in modifying testosterone action and this has important implications for the role of SHBG in health and disease.
| S-EPMC5136390 | biostudies-literature
Project description:BackgroundLevels of sex hormone-binding globulin (SHBG) and the androgen testosterone have been associated with risk of diseases throughout the lifecourse. Although both SHBG and testosterone have been shown to be highly heritable, only a fraction of that heritability has been explained by genetic studies. Epigenetic modifications such as DNA methylation may explain some of the missing heritability and could potentially inform biological knowledge of endocrine disease mechanisms involved in development of later life disease. Using data from the Avon Longitudinal Study of Parents and Children (ALSPAC), we explored cross-sectional associations of SHBG, total testosterone and bioavailable testosterone in childhood (males only) and adolescence (both males and females) with genome-wide DNA methylation. We also report associations of a SHBG polymorphism (rs12150660) with DNA methylation, which leads to differential levels of SHBG in carriers, as a genetic proxy of circulating SHBG levels.ResultsWe identified several novel sites and genomic regions where levels of SHBG, total testosterone, and bioavailable testosterone were associated with DNA methylation, including one region associated with total testosterone in males (annotated to the KLHL31 gene) in both childhood and adolescence and a second region associated with bioavailable testosterone (annotated to the CMYA5 gene) at both time-points. We also identified one region where both SHBG and bioavailable testosterone in males in childhood (annotated to the ZNF718 gene) was associated with DNA methylation.ConclusionOur findings have important implications in the understanding of the biological processes of SHBG and testosterone, with the potential for future work to determine the molecular mechanisms that could underpin these associations.
| S-EPMC6295101 | biostudies-literature
Project description:ObjectiveRegulators of adipose tissue hormones remain incompletely understood, but may include sex hormones. As adipose tissue hormones have been shown to contribute to numerous metabolic and cardiovascular disorders, understanding their regulation in midlife women is of clinical importance. Therefore, we assessed the associations between testosterone (T) and sex hormone binding globulin (SHBG) with leptin, high molecular weight (HMW) adiponectin, and the soluble form of the leptin receptor (sOB-R) in healthy midlife women.Design and methodsCross-sectional analyses were performed using data from 1,881 midlife women (average age 52.6 (±2.7) years) attending the sixth Annual follow-up visit of the multiethnic Study of Women's Health Across the Nation.ResultsT was weakly negatively associated with both HMW adiponectin and sOB-R (r = -0.12 and r = -0.10, respectively; P < 0.001 for both), and positively associated with leptin (r = 0.17; P < 0.001). SHBG was more strongly and positively associated with both HMW adiponectin and sOB-R (r = 0.29 and r = 0.24, respectively; P < 0.001 for both), and more strongly and negatively associated with leptin (r = -0.27; P < 0.001). Adjustment for fat mass, insulin resistance, or waist circumference only partially diminished associations with HMW adiponectin and sOB-R, but attenuated associations with leptin. In conclusion, in these midlife women, lower SHBG values, and to a lesser extent, higher T levels, were associated with lower, or less favorable, levels of adiponectin and sOB-R, independent of fat mass.ConclusionsThese data suggest that variation in these adipose hormones resulting from lower SHBG levels, and possibly, though less likely, greater androgenicity, may contribute to susceptibility for metabolic and cardiovascular outcomes during midlife in women.
| S-EPMC4109046 | biostudies-literature
Project description:Genome-wide association studies (GWAS) have successfully identified common genetic variants that contribute to breast cancer risk. Discovering additional variants has become difficult, as power to detect variants of weaker effect with present sample sizes is limited. An alternative approach is to look for variants associated with quantitative traits that in turn affect disease risk. As exposure to high circulating estradiol and testosterone, and low sex hormone-binding globulin (SHBG) levels is implicated in breast cancer etiology, we conducted GWAS analyses of plasma estradiol, testosterone, and SHBG to identify new susceptibility alleles. Cancer Genetic Markers of Susceptibility (CGEMS) data from the Nurses' Health Study (NHS), and Sisters in Breast Cancer Screening data were used to carry out primary meta-analyses among ~1600 postmenopausal women who were not taking postmenopausal hormones at blood draw. We observed a genome-wide significant association between SHBG levels and rs727428 (joint ? = -0.126; joint P = 2.09 × 10(-16)), downstream of the SHBG gene. No genome-wide significant associations were observed with estradiol or testosterone levels. Among variants that were suggestively associated with estradiol (P<10(-5)), several were located at the CYP19A1 gene locus. Overall results were similar in secondary meta-analyses that included ~900 NHS current postmenopausal hormone users. No variant associated with estradiol, testosterone, or SHBG at P<10(-5) was associated with postmenopausal breast cancer risk among CGEMS participants. Our results suggest that the small magnitude of difference in hormone levels associated with common genetic variants is likely insufficient to detectably contribute to breast cancer risk.
| S-EPMC3366971 | biostudies-literature
Project description:ObjectiveWe sought to assess the associations of testosterones and sex hormone-binding globulin (SHBG) with metabolic syndrome and insulin resistance in men.Research design and methodsWe defined metabolic syndrome according to the National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Among men aged >or=20 years who participated in the Third National Health and Nutrition Examination Survey (n = 1,226), the Cox proportional hazards model was used to estimate the prevalence ratio and 95% CI of metabolic syndrome according to circulating concentrations of testosterones and SHBG.ResultsAfter adjustment for age, race/ethnicity, smoking status, alcohol intake, physical activity level, LDL cholesterol, C-reactive protein, and insulin resistance, men in the first quartile (lowest) (prevalence ratio 2.16 [95% CI 1.53-3.06]) and second quartile of total testosterone (2.51 [1.86-3.37]) were more likely to have metabolic syndrome than men in the fourth quartile (highest, referent group) (P < 0.001 for linear trend). Similarly, men in the first quartile of SHBG (2.17 [1.32-3.56]) were more likely to have metabolic syndrome than men in the fourth quartile (P = 0.02 for linear trend). No significant associations of calculated free testosterone (P = 0.31 for linear trend) and bioavailable testosterone (P = 0.11 for linear trend) with metabolic syndrome were detected after adjustment for all possible confounders.ConclusionsLow concentrations of total testosterone and SHBG were strongly associated with increased likelihood of having metabolic syndrome, independent of traditional cardiovascular risk factors and insulin resistance.
| S-EPMC2890370 | biostudies-literature
Project description:BACKGROUND AND AIMS:The cortisol/testosterone (C/T) ratio has been hypothesized to be a better predictor of atherosclerosis than cortisol alone. No study has assessed whether the C/T and C/sex hormone-binding globulin (SHBG) ratios are associated with atherosclerosis in a U.S. population sample. METHODS:This substudy included 367 women who had both cortisol from year 15 and testosterone and SHBG at year 16 of the Coronary Artery Risk Development in Young Adults study, an ongoing observational cohort in the United States. Of these, intima-media thickness (IMT) was available at follow-up year 20 in 339 (n = 332 with measurement at carotid bulb), and 303 were free of prevalent coronary artery calcium (CAC) at year 15. Area under the curve (AUC) of salivary cortisol was available in 302 individuals. Ratios of AUCs of cortisol to total testosterone, free testosterone, and SHBG were categorized into tertiles. Associations with CAC and IMT were assessed by regression models adjusted for age, race, body mass index, systolic blood pressure, menopause, oral contraceptive use, diabetes, alcohol, and smoking. RESULTS:Only the highest tertile of the AUC/free testosterone ratio was positively associated with carotid bulb IMT (? = 0.088, P = 0.006). This tertile was also positively associated with new onset CAC between year 15 and 25 (OR 3.45, 95% CI 1.18-10.06). Tertiles of cortisol or testosterone alone were not associated with new onset CAC. CONCLUSION:AUC/Free testosterone ratio may be more associated with atherosclerosis in women than either indicator alone. The ratio may serve as a suitable biomarker of cortisol-linked stress.
| S-EPMC5819892 | biostudies-literature
Project description:BackgroundEpidemiologic studies evaluating associations between sex steroid hormones and colorectal cancer risk have yielded inconsistent results. To elucidate the role of circulating levels of testosterone, and sex hormone-binding globulin (SHBG) in colorectal cancer risk, we conducted observational and Mendelian randomization (MR) analyses.MethodsThe observational analyses included 333,530 participants enrolled in the UK Biobank with testosterone and SHBG measured. HRs and 95% confidence intervals (CI) were estimated using multivariable Cox proportional hazards models. For MR analyses, genetic variants robustly associated with hormone levels were identified and their association with colorectal cancer (42,866 cases/42,752 controls) was examined using two-sample MR.ResultsIn the observational analysis, there was little evidence that circulating levels of total testosterone were associated with colorectal cancer risk; the MR analyses showed a greater risk for women (OR per 1-SD = 1.09; 95% CI, 1.01-1.17), although pleiotropy may have biased this result. Higher SHBG concentrations were associated with greater colorectal cancer risk for women (HR per 1-SD = 1.16; 95% CI, 1.05-1.29), but was unsupported by the MR analysis. There was little evidence of associations between free testosterone and colorectal cancer in observational and MR analyses.ConclusionsCirculating concentrations of sex hormones are unlikely to be causally associated with colorectal cancer. Additional experimental studies are required to better understand the possible role of androgens in colorectal cancer development.ImpactOur results from large-scale analyses provide little evidence for sex hormone pathways playing a causal role in colorectal cancer development.See related commentary by Hang and Shen, p. 1302.
| S-EPMC8914241 | biostudies-literature