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 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.