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.
Highlights
follicle-stimulating hormone receptor (FSHR) single nucleotide polymorphisms (SNPs) may influence the ovarian sensitivity to endogenous and exogenous Follicle-stimulating hormone (FSH) stimulation
In women from the IVF cohort, we found a higher GG genotype frequency of the FSHR c.2039A > G SNP than those previously reported in placental samples from Mexican mestizo women [23] as well as in the 1000 Genomes Project Phase 3 database [32](http:// grch37.ensembl.org/) for a small cohort of Hispanic subjects residing in Los Angeles, CA, USA, of presumptive Mexican ancestry, but still markedly lower than in Caucasians, in whom the frequency range from ~ 20% to ~ 36% [6]
The frequency of the S680S FSHR variant observed in the present study, was lower than that reported in Colombians (~ 14%)(http://grch37.ensembl.org/), in whom the estimated African and European genetic admixture proportions are higher than in Mexicans (11% vs. 5% and 60% vs. 37%, respectively) [42], emphasizing on the substantial impact of the admixture with Spaniards on the c.2039A > G FSHR SNP in Latin America
Summary
FSHR SNPs may influence the ovarian sensitivity to endogenous and exogenous FSH stimulation. Follicle-stimulating hormone (FSH), one of the gonadotrophins synthesized by the pituitary gland, plays a pivotal role in reproduction. This gonadotrophin binds its cognate receptor, the follicle-stimulating hormone receptor (FSHR), in the granulosa cells of the ovarian follicles and the Sertoli cells lining the seminiferous tubules of the testes, to regulate an array of biological effects associated with reproductive competence. Of the nearly 2000 single nucleotide polymorphisms (SNPs) of the FSHR, five are located in exon 10 [3]. Four of these SNPs are non-synonymous and lead to amino acid substitution, resulting in the T307A, R524S, A665T, and N680S FSHR protein variants [4, 5]. The most common and best studied SNPs of this receptor are c.919A > G (rs6165) and c.2039A > G (rs6166), which are inherited in strong linkage disequilibrium [at least in Caucasians and Asians and less in Africans [6]] and whose most common FSHR variants, T307/N680 and A307/S680, are almost distributed among Europeans [3, 6,7,8,9]
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