SHBG gene polymorphisms and their influence on serum SHBG, total and free testosterone concentrations in men

Joeri Walravens; Bas Sleumer; Michel J Vos; Gido Snaterse; Nick Narinx; Leen Antonio; Tim Reyns; Tom Fiers; Ido P Kema; Jean-Marc Kaufman; Nico C van de Merbel; Bruno Lapauw

doi:10.1210/clinem/dgae280

SHBG gene polymorphisms and their influence on serum SHBG, total and free testosterone concentrations in men

J Clin Endocrinol Metab. 2024 Apr 23:dgae280. doi: 10.1210/clinem/dgae280. Online ahead of print.

Authors

Joeri Walravens¹, Bas Sleumer^{2

3

4}, Michel J Vos⁴, Gido Snaterse¹, Nick Narinx⁵, Leen Antonio⁵, Tim Reyns⁶, Tom Fiers⁶, Ido P Kema⁴, Jean-Marc Kaufman¹, Nico C van de Merbel^{2

3}, Bruno Lapauw¹

Affiliations

¹ Department of Endocrinology, Ghent University Hospital, Corneel Heymanslaan 10, 9000 Ghent, Belgium.
² ICON Bioanalytical Laboratories, Amerikaweg 18, 9407 TK, Assen, The Netherlands.
³ Department of Analytical Biochemistry University of Groningen, A. Deusinglaan 1, 9700 AV Groningen, The Netherlands.
⁴ Department of Laboratory Medicine, University of Groningen, University Medical Center Groningen, EA61, P.O. Box 30.001, 9700 RB Groningen, The Netherlands.
⁵ Laboratory of Clinical and Experimental Endocrinology, KULeuven, Herestraat 49, 3000 Leuven, Belgium.
⁶ Department of Clinical Chemistry, Ghent University Hospital, Corneel Heymanslaan 10, 9000 Ghent, Belgium.

PMID: 38652149
DOI: 10.1210/clinem/dgae280

Abstract

Context: Genetic variation in sex hormone-binding globulin (SHBG) structure may affect estimates of sex steroid exposure by altering the affinity of the protein for its ligand. Consequently, free hormone calculations assuming constant binding affinity may, for certain genetic variations, lead to incorrect diagnoses if genetic variation is not taken into consideration.

Objective: To investigate the effects of genetic variation in SHBG on calculated and measured serum free testosterone (T) in men.

Design, setting and participants: Population-based sibling-pair study in 999 healthy men aged 25 to 45 (mean: 34.5) years.

Main outcome measures: Genotyping using microarray (Illumina®) for SNPs suggested to affect binding affinity and/or concentration of SHBG or T. SHBG concentrations were measured using immunoassay and in a subset (n = 32) by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Total T was measured using LC-MS/MS. Free T was calculated and in a subset (n = 314) measured directly using LC-MS/MS after equilibrium dialysis.

Results: Allelic frequencies of analyzed SNPs ranged from 0.5% to 58.2%. Compared to wild-type, SHBG concentrations were lower in rs6258 heterozygotes (-24.7%; p < 0.05) and higher in rs6259 heterozygotes, rs727428 homozygotes, and carriers of rs1799941 (+10.8 to 23.1%; all p < 0.05). Total T was higher in rs727428 homozygotes and carriers of rs5934505, rs1799941and rs6259 (+3.9 to 21.4%; all p < 0.05). No clear effects on measured free T were found, except for a trend towards higher values in rs6259 homozygotes, significant for calculated free T (+18.7%; p < 0.05) in the larger global study population.

Conclusion: In these men, analyzed SNPs were relatively prevalent and affected serum concentrations of total T and SHBG but not calculated or measured free T except for a higher trend in rs6259 homozygotes.

Keywords: LC-MS/MS; SHBG; free testosterone; healthy men; polymorphisms; testosterone.

© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.