Frequency of the T307A, N680S, and -29G>A single-nucleotide polymorphisms in the follicle-stimulating hormone receptor in Mexican subjects of Hispanic ancestry

Abstract

BackgroundFSHR SNPs may influence the ovarian sensitivity to endogenous and exogenous FSH stimulation. Given the paucity of data on the FSHR c.919A > G, c.2039A > G and − 29G > A SNPs in Hispanic population, we here analyzed their frequency distribution in Mexican mestizo women.MethodsSamples from 224 Mexican mestizo women enrolled in an IVF program as well as a genotype database from 8182 Mexican mestizo subjects, were analyzed for FSHR SNPs at positions c.919, c.2039 and − 29G > A. Association between the genetic variants and reproductive outcomes was assessed.ResultsThe c.919 and c.2039 SNPs were in strong linkage disequilibrium and their corresponding genotype frequencies in the IVF group were: AA 46.8%, AG 44.2%, and GG 8.9%, and AA 41.9%, AG 48.2% and GG 9.8%, respectively. For the -29G > A SNP, genotype frequencies were 27% (GG), 50% (GA) and 23% (AA). In normal oocyte donors with the c.2039 GG genotype, the number of oocytes recovered after ovarian stimulation (COS) were significantly (p < 0.01) lower than in those bearing other genotypes in this or the -29G > A SNP. Analysis of the large scale database revealed that both allelic and genotype frequencies for the three SNPs were very similar to those detected in the IVF cohort (p ≥ 0.38) and that female carriers of the c.2039 G allele tended to present lower number of pregnancies than women bearing the AA genotype; this trend was stronger when women with more Native American ancestry was separately analyzed (OR = 2.0, C.I. 95% 1.03–3.90, p = 0.04). There were no differences or trends in the number of pregnancies among the different genotypes of the -29G > A SNP.ConclusionsThe frequency of the GG/GG combination genotype for the c.919 and c.2039 SNPs in Mexican hispanics is among the lowest reported. The GG genotype is associated with decreased number of oocytes recovered in response to COS as well as to lower pregnancy rates in Hispanic women from the general population. The absence of any effect of the -29AA genotype on the response to COS, indicates that there is no need to perform this particular genotype testing in Hispanic women with the purpose of providing an individually-tailored COS protocol.Electronic supplementary materialThe online version of this article (10.1186/s12958-018-0420-4) contains supplementary material, which is available to authorized users.

Pharmacogenetics of FSH Action in the Female

“…Indeed, we found that GG FSH-R ( RS6166 ) carriers had higher ovarian resistance to exogenous gonadotropin and, consequently, had fewer oocytes compared with AA carriers (15). These findings were also confirmed in a more recent study (31). In addition, higher FSH basal levels and resistance to clomiphene citrate were observed in G allele carriers, supporting an higher receptorial resistance even to endogenous level of FSH (15, 27, 48, 49).…”

“…This observation was confirmed in a further larger study by Desai et al involving 100 women (16) where those with the AA genotype at position−29 were at higher risk for poor ovarian response in comparison to the other haplotypes (OR 8.63, 95% CI 1.84–45.79; P = 0.001). In contrast, other authors did not confirm significant effects of this variant concerning the ovarian response (31, 32, 51). The evidence regarding the clinical effect of the FSH-R − 29 G > A ( RS1394205 ) variant on OS was summarized in a recent meta-analysis, which showed that higher exogenous FSH consumption is required in homozygotes for the A allele than carriers of the G allele (15).…”

Structure-Function Relationships of the Follicle-Stimulating Hormone Receptor

“…Expression of the S680S FSHR variant in vivo has been associated with variations in the sensitivity of the FSHR to its cognate ligand ( 158 , 159 ), whereas in vitro this variant exhibited attenuated intracellular signaling kinetics, enhanced β-arresting recruitment and ligand-stimulated internalization, and decreased CREB-dependent gene transcription and nuclear PKA activation ( 160 , 161 ). The functional abnormalities of the S680S FSHR variant might be responsible for the altered response to exogenous FSH administration presented by women bearing the homozygous state as well as for the lower pregnancy rates observed in some particular populations ( 162 ).…”

Pharmacogenomic Biomarkers of Follicle-Stimulating Hormone Receptor Malfunction in Females with Impaired Ovarian Response—A Genetic Survey

“…For instance, Ilgaz et al showed there are no significant differences between infertile women and healthy controls for the Asn680Ser variant in the Turkish population, and the genotype landscape is consistent for both groups [ 36 ]. In addition, García-Jiménez and colleagues from Mexico indicated a non-significant association between 5′ UTR g.-29G>A and ovary response in IVF-treated women with controlled ovarian stimulation (COS) [ 69 ]. However, most of the investigations indicated lower effects of altered FSHR function on the overall rate of ovarian stimulation and also, the number of studies for ethnic differences in FSHR responses is not high.…”