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.卵泡刺激素受体（Follicle-Stimulating Hormone Receptor, FSHR）-29G/A多态性（rs1394205）据报道可调节女性的基因表达与生殖参数，但目前针对男性的相关研究数据较为有限。本研究旨在为FSHR -29G/A变异在男性中的作用提供证据。我们纳入了波罗的海青年男性队列（n=982；受试者为爱沙尼亚人、拉脱维亚人、立陶宛人，年龄20.2±2.0岁），结果显示FSHR -29 A等位基因与较高的血清卵泡刺激素（FSH）水平显著相关（线性回归分析：效应值0.27 IU/L；P=0.0019，经多重检验的邦费罗尼校正后仍具有统计学意义），同时呈现出与较高黄体生成素（LH，0.19 IU/L）及总睾酮（0.93 nmol/L）相关的非显著趋势，但与抑制素B水平降低（−7.84 pg/mL）及总睾丸体积减小（效应值−1.00 mL）相关。随后，我们拓展了研究范围，针对由FSHR -29G/A与另一研究充分的变异c.2039 A/G（Asn680Ser，外显子10）的等位基因组合所确定的FSHR基因单倍型进行了效应检测。在携带FSHR -29A/2039G单倍型的受试者中（A-Ser；基于单倍型的线性回归分析），该遗传效应对FSH（效应值0.40 IU/L）、抑制素B（−16.57 pg/mL）及总睾丸体积（−2.34 mL）的影响更为显著。最后，我们评估了三种已知的调节FSH作用的单核苷酸多态性（Single Nucleotide Polymorphism, SNP）——FSHB -211G/T、FSHR -29G/A及c.2039 A/G——对青年男性生殖参数表型变异的总贡献度。这三类主要的调节FSH作用的SNP联合解释了血清FSH、抑制素B、睾酮及总睾丸体积测量变异的2.3%、1.4%、1.0%及1.1%。与青年男性队列不同，FSHR -29G/A多态性或FSHR单倍型均未对少精子症特发性不育患者（n=641，为爱沙尼亚人，年龄31.5±6.0岁）的生殖生理产生系统性调节作用。综上，本研究首次证实了FSHR -29G/A多态性对男性血清FSH水平具有显著影响。为充分考虑已知的常见调节FSH作用的多态性的遗传效应，我们建议将FSHR单核苷酸多态性（FSHR -29G/A、c.2039 A/G）的基于单倍型的分析与FSHB -211G/T检测相结合。