Genetics of Sex Hormone-Binding Globulin and Testosterone Levels in Fertile and Infertile Men of Reproductive Age
| Autor: | Vladimir Vihljajev, Marina Grigorova, Mart Adler, Margus Punab, Maris Laan, Olev Poolamets |
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| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
medicine.medical_specialty 030219 obstetrics & reproductive medicine biology business.industry Endocrinology Diabetes and Metabolism Context (language use) medicine.disease Male infertility 03 medical and health sciences 030104 developmental biology 0302 clinical medicine Sex hormone-binding globulin Endocrinology Transgender hormone therapy Reproductive Biology and Sex-Based Medicine Internal medicine biology.protein Medicine business Luteinizing hormone Pharmacogenetics Testosterone Hormone Research Article |
| Zdroj: | Journal of the Endocrine Society |
| ISSN: | 2472-1972 |
| Popis: | 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 Measure(s): 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. Only four of seven top-associated SNPs from GWAS meta-analysis for serum SHBG and T were robustly replicated in fertile and infertile men of reproductive age, representing SHBG and GCKR gene variants. |
| Databáze: | OpenAIRE |
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