Dataset Information

Genetics of Sex Hormone-Binding Globulin and Testosterone Levels in Fertile and Infertile Men of Reproductive Age.

ABSTRACT: Context:Testosterone (T) is a central androgenic hormone, and sex hormone-binding globulin (SHBG) is the major determinant of its bioactivity. There are no acknowledged genetic variants with clear-cut clinical implications, modulating T levels in men. Objective:To confirm genetic associations of top loci (SHBG, GCKR, SLCO1B1, and JMJD1C) from genome-wide association (GWA) studies for serum SHBG and T. Design Patients:Groups differing in general and reproductive parameters: young men (n = 540; 19.3 ± 1.8 years), severe idiopathic male infertility patients (n = 641; 31.6 ± 6.0 years), and male partners of pregnant women (n = 324; 31.9 ± 6.6 years). All patients were recruited at the Andrology Centre, Tartu University Hospital, Estonia. Main Outcome Measures:Genetic associations with reproductive hormones, testicular and sperm parameters (linear regression, additive model); intergroup allele/genotype distribution comparisons. Results:Associations with serum SHBG levels were robust for SHBG -68 G>A [rs1799941; meta-analysis: P = 3.7 × 10-14; allelic effect (standard error) = 4.67 (0.62) nmol/L], SHBG +1091 C>T [rs727428; P = 7.3 × 10-11; -3.74 (0.57)], SHBG Pro185Leu [rs6258; P = 1.2 × 10-4, -12.2 (3.17)], and GCKR Pro446Leu [rs1260326; P = 1.5 × 10-4; -2.2 (0.59)]. Measured T concentrations correlated with genetically modulated levels of SHBG (r = 0.48 to 0.74, P < 0.0001), guaranteeing stable availability of free T. Among infertile men, SHBG Pro185Leu substitution showed additional downstream effect on luteinizing hormone [P = 5.1 × 10-5; -1.66 (0.57) IU/L] and follicle-stimulating hormone [P = 3.4 × 10-3; -2.48 (1.23) IU/L]. No associations with male reproductive parameters were detected for SHBG Asp327Asn (rs6259), SLCO1B1 Val174Ala (rs4149056), and JMJD1C intronic variant rs7910927. Conclusions:Claims were replicated and additional associations were detected for four of seven tested GWAS top loci. Perspective clinical investigations of these variants are hypotestosteronemia among aging men and pharmacogenetics of hormone replacement therapy.

SUBMITTER: Grigorova M

PROVIDER: S-EPMC5686641 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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Genetics of Sex Hormone-Binding Globulin and Testosterone Levels in Fertile and Infertile Men of Reproductive Age.

Grigorova Marina M Punab Margus M Poolamets Olev O Adler Mart M Vihljajev Vladimir V Laan Maris M

Journal of the Endocrine Society 20170411 6

<h4>Context</h4>Testosterone (T) is a central androgenic hormone, and sex hormone-binding globulin (SHBG) is the major determinant of its bioactivity. There are no acknowledged genetic variants with clear-cut clinical implications, modulating T levels in men.<h4>Objective</h4>To confirm genetic associations of top loci (<i>SHBG</i>, <i>GCKR</i>, <i>SLCO1B1</i>, and <i>JMJD1C</i>) from genome-wide association (GWA) studies for serum SHBG and T.<h4>Design patients</h4>Groups differing in general a ...[more]

PMID: 29264510

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Project description:Decreased total testosterone (TT) is the recommended metric to identify age-related hypogonadism. However, average TT and the extent to which it varies by age, can vary substantially among different populations. Population-specific reference ranges are needed to understand normal versus abnormal TT levels. Therefore, the goal for this study was to describe androgen concentrations and their correlates among Western Chinese men. We completed a population-based, cross-sectional study including 227 young adults (YA) (20-39 years) and 939 older adults (OA) (40-89 years). We measured TT, sex-hormone binding globulin (SHBG), luteinizing hormone (LH), testosterone secreting index (TSI), and calculated free testosterone (cFT). Reference ranges for this population were determined using average YA concentrations. Multivariable regression models were used to predict hormone concentrations adjusting for age, waist-to-height ratio (WHR), marital status, education, occupation, smoking, alcohol, blood glucose, and blood pressure. Among OA, 3.8% had low TT, 15.2% had low cFT, 26.3% had low TSI, 21.6% had high SHBG, and 6.1% had high LH. Average cFT was significantly lower in OA (0.30 nmol/L; standard deviation (SD): 0.09) versus YA (0.37; SD: 0.11) but TT was not different in OA (16.82 nmol/L; SD: 4.80) versus YA (16.88; SD: 5.29). In adjusted models increasing age was significantly associated with increased SHBG or LH, and decreased cFT or TSI; however, TT was not significantly associated with age (β = 0.02 nmol/L; 95% confidence interval (CI): -0.01, 0.04). Higher WHR was associated with significantly decreased TT, SHBG, TSI, and LH. The only variable significantly related to cFT was age (β = -0.0033; 95% CI:-0.0037, -0.0028); suggesting that cFT measurements would not be confounded by other lifestyle factors. In conclusion, cFT, but not TT, varies with age in this population, suggesting cFT may be a better potential marker for age-related androgen deficiency than TT among Western Chinese men.

Dataset Information

Genetics of Sex Hormone-Binding Globulin and Testosterone Levels in Fertile and Infertile Men of Reproductive Age.

Publications

Genetics of Sex Hormone-Binding Globulin and Testosterone Levels in Fertile and Infertile Men of Reproductive Age.

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