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

Marina Grigorova; Margus Punab; Olev Poolamets; Mart Adler; Vladimir Vihljajev; Maris Laan

doi:10.1210/js.2017-00050

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

J Endocr Soc. 2017 Apr 11;1(6):560-576. doi: 10.1210/js.2017-00050. eCollection 2017 Jun 1.

Authors

Marina Grigorova^{1

2}, Margus Punab³, Olev Poolamets³, Mart Adler^{1

3}, Vladimir Vihljajev³, Maris Laan^{1

2}

Affiliations

¹ Institute of Biomedicine and Translational Medicine, University of Tartu, 50411 Tartu, Estonia.
² Human Molecular Genetics Research Group, Institute of Molecular and Cell Biology, University of Tartu, 51010 Tartu, Estonia.
³ Andrology Unit, Tartu University Hospital, 50406 Tartu, Estonia.

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.