Impact of SNP on hormone function: FSH receptor
The FSHR is characterised by a large number of SNPs (1636 listed in the NCBI SNP database), mostly located in intronic regions and of unknown heterozygosity rate. Some SNPs, especially those which are nonsynonymous and located in exons have been studied in association with gonadal function.
The SNPs at nt position 919 and 2039 in exon 10 are very common (heterozygosity: 0.469) and result in the aminoacid transition Thr/Ala at codon 307 and Asn/Ser at codon 680, respectively. In the Caucasian population they are in linkage disequilibrium with the Thr307-Asn680 variant covering 55% and the Ala307-Ser680 variant 45% of the alleles. The other two possible combinations represent <1% of all alleles in Caucasians, while they are more frequent in the East. A G/A SNP is located in the promoter region (−29), with the G allele covering 75% and the A allele 25% of the alleles in Caucasians, while the distribution is equal (50%) in Indonesians. These SNPs do not have any apparent functional effect in vitro, but influence the receptor activity in vivo, at least in women. We could show that the Ala307-Ser680 variant is associated with higher basal serum FSH levels and lower sensitivity to FSH stimulation in women with normal ovarian function undergoing ovarian hyper stimulation for assisted reproduction and during normal menstrual cycle. However, these two SNP apparently do not influence serum FSH levels and semen parameters in men with normal or reduced spermatogenesis. However, when the haplotypes resulting from the SNPs in exon 10 and from the SNP at position −29 in the promoter region are considered together the two allelic variants A-Ala-Ser and G-Thr-Asn showed a statistically significant different distribution between controls and men with non-obstructive azoospermia, suggesting that the FSHR genotype might constitute a risk factor for spermatogenetic failure.