Identification of common genetic polymorphisms associated with down-regulated gonadotropin levels in an exome-wide association study

摘要

Objective: To investigate whether common genetic polymorphisms are associated with gonadotropin levels after down-regulation with daily gonadotropin-releasing hormone agonist and whether the polymorphisms of candidate variants influence the ovarian response to exogenous gonadotropins. @@@ Design: Genetic association study. @@@ Setting: University-affiliated in vitro fertilization center. @@@ Patients: Subjects enrolled in an exploratory exome-wide association study (n= 862), a replication exome-wide association study (n= 86), and a classifier validation study (n= 148) were recruited from September 2016 to October 2018, September 2019 to September 2020, and January 2021 to December 2021, respectively. The included patients were aged %40 years and had a basal follicle-stimulating hormone (FSH) %12 IU/L. @@@ Interventions: All participants received a luteal phase down-regulation long protocol. Genome DNA was extracted from the peripheral blood leukocytes. For the exploratory and replication cohorts, exome sequencing was conducted on a HiSeq 2500 sequencing platform. The multiplex polymerase chain reaction amplification technique and next-generation sequencing also were performed in the exploratory and replication cohorts. For the samples of the validation cohort, Sanger sequencing was performed. @@@ Main Outcome Measures: The primary endpoint was the gonadotropin levels after down-regulation, and the secondary endpoints were hormone levels and follicle diameters during stimulation, the total dose of FSH, duration of FSH stimulation, number of oocytes retrieved, and clinical pregnancy rate. @@@ Results: In the exploratory cohort, we identified that FSHB rs6169 (P=2.71 x 10(-24)) and its single-nucleotide polymorphisms in high linkage disequilibrium were associated with the down-regulated FSH level. The same locus was confirmed in the replication cohort. Women carrying the C allele of FSHB rs6169 exhibited higher average estradiol level during stimulation (P=6.82 x 10(-5)), shorter duration of stimulation, and less amount of exogenous FSH (P-duration=0.0002; P-dose=0.0024). In the independent validation set, adding rs6169 genotypes into the prediction model for FSH level after down-regulation enhanced the area under the curve from 0.560 to 0.712 in a logistic regression model, and increased prediction accuracy by 41.05% when a support vector machine classifier was applied. @@@ Conclusion: The C allele of FSHB rs6169 is a susceptibility site for the relatively high level of FSH after down-regulation, which may be associated with increased ovarian FSH sensitivity. (Fertil Steril (R) 2023;120:671-81.

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