Ovulation induction is a first-line medical treatment for infertility in polycystic ovary syndrome (PCOS). Poor ovulation responses are assumed to be due to insulin resistance and hyperandrogenism. In a prospective cohort (PCOSAct) of 1000 infertile patients with PCOS, whole-exome plus targeted single-nucleotide polymorphism (SNP) sequencing and comprehensive metabolomic profiling were conducted. Significant genome-wide common variants and rare mutations associated with anovulation were identified, and a prediction model was built using machine learning. Common variants in zinc-finger protein 438 gene (ZNF438) indexed by rs2994652 (p = 2.47 × 10–8) and a rare functional mutation in REC114 (rs182542888, p = 5.79 × 10–6) were significantly associated with failure of ovulation induction. Women carrying the A allele of rs2994652 and REC114 p.Val101Leu (rs182542888) had lower ovulation (odds ratio (OR) = 1.96, 95% confidence interval (95%CI) = 1.55–2.49; OR = 11.52, 95%CI = 3.08–43.05, respectively) and prolonged time to ovulation (mean = 56.7 versus (vs) 49.0 days, p < 0.001; 78.1 vs 68.6 days, p = 0.014, respectively). L-phenylalanine was found to be increased and correlated with the Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) index (r = 0.22, p = 0.050) and fasting glucose (r = 0.33, p = 0.003) for rs2994652, while arachidonic acid metabolism was found to be decreased and associated with increased anti-Müllerian hormone (AMH; r = –0.51, p = 0.01) and total testosterone (TT; r = –0.71, p = 0.02) for rs182542888. A combined model of genetic variants, metabolites, and clinical features increased the prediction of ovulation (area under the curve (AUC) = 76.7%). Common variants in ZNF438 and rare functional mutations in REC114, associated with phenylalanine and arachidonic acid metabolites, contributed to the failure of infertility treatment in women with PCOS.
All Science Journal Classification (ASJC) codes
- Computer Science(all)
- Environmental Engineering
- Chemical Engineering(all)
- Materials Science (miscellaneous)
- Energy Engineering and Power Technology