Reproductive physiology in young men is cumulatively affected by FSH-action modulating genetic variants: FSHR -29G/A and c.2039 A/G, FSHB -211G/T.
Follicle-Stimulating Hormone Receptor (FSHR) -29G/A polymorphism (rs1394205) was reported to modulate gene expression and reproductive parameters in women, but data in men is limited. We aimed to bring evidence to the effect of FSHR -29G/A variants in men. In Baltic young male cohort (n = 982; Estonians, Latvians, Lithuanians; aged 20.2 ± 2.0 years), the FSHR -29 A-allele was significantly associated with higher serum FSH (linear regression: effect 0.27 IU/L; P = 0.0019, resistant to Bonferroni correction for multiple testing) and showed a non-significant trend for association with higher LH (0.19 IU/L) and total testosterone (0.93 nmol/L), but reduced Inhibin B (-7.84 pg/mL) and total testes volume (effect -1.00 mL). Next, we extended the study and tested the effect of FSHR gene haplotypes determined by the allelic combination of FSHR -29G/A and a well-studied variant c.2039 A/G (Asn680Ser, exon 10). Among the FSHR -29A/2039G haplotype carriers (A-Ser; haplotype-based linear regression), this genetic effect was enhanced for FSH (effect 0.40 IU/L), Inhibin B (-16.57 pg/mL) and total testes volume (-2.34 mL). Finally, we estimated the total contribution of three known FSH-action modulating SNPs (FSHB -211G/T; FSHR -29G/A, c.2039 A/G) to phenotypic variance in reproductive parameters among young men. The major FSH-action modulating SNPs explained together 2.3%, 1.4%, 1.0 and 1.1% of the measured variance in serum FSH, Inhibin B, testosterone and total testes volume, respectively. In contrast to the young male cohort, neither FSHR -29G/A nor FSHR haplotypes appeared to systematically modulate the reproductive physiology of oligozoospermic idiopathic infertile patients (n = 641, Estonians; aged 31.5 ± 6.0 years). In summary, this is the first study showing the significant effect of FSHR -29G/A on male serum FSH level. To account for the genetic effect of known common polymorphisms modulating FSH-action, we suggest haplotype-based analysis of FSHR SNPs (FSHR -29G/A, c.2039 A/G) in combination with FSHB -211G/T testing.
Human Molecular Genetics Research Group, Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia.
Marina
M
Grigorova
Andrology Unit, Tartu University Hospital, Tartu, Estonia.
Margus
M
Punab
Human Molecular Genetics Research Group, Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia.
Anna Maria
AM
Punab
Andrology Unit, Tartu University Hospital, Tartu, Estonia.
Olev
O
Poolamets
Andrology Unit, Tartu University Hospital, Tartu, Estonia.
Vladimir
V
Vihljajev
Institute of Endocrinology, Medical Academy, Lithuanian University of Health Sciences, Kaunas, Lithuania.
Birutė
B
Zilaitienė
Andrology Laboratory, Riga Stradins University, Riga, Latvia.
Juris
J
Erenpreiss
Institute of Endocrinology, Medical Academy, Lithuanian University of Health Sciences, Kaunas, Lithuania.
Valentinas
V
Matulevičius
Human Molecular Genetics Research Group, Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia.
Maris
M
Laan
D020121:5' Untranslated Regions / Q000235:genetics; D000483:Alleles; D001454:Baltic States; D043373:Follicle Stimulating Hormone, Human / Q000097:blood*; D037201:Follicle Stimulating Hormone, beta Subunit / Q000235:genetics / Q000502:physiology*; D014644:Genetic Variation; D006239:Haplotypes; D006801:Humans; D007265:Inhibins / Q000097:blood*; D008297:Male; D009845:Oligospermia / Q000097:blood / Q000208:ethnology / Q000235:genetics*; D009929:Organ Size; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011962:Receptors, FSH / Q000235:genetics / Q000502:physiology*; D013737:Testis / Q000473:pathology*; D013739:Testosterone / Q000097:blood*; D055815:Young Adult
D020121:5' Untranslated Regions; D043373:Follicle Stimulating Hormone, Human; D037201:Follicle Stimulating Hormone, beta Subunit; D011962:Receptors, FSH; C422364:inhibin B; D013739:Testosterone; D007265:Inhibins