Novel Genetic Risk and Metabolic Signatures of Insulin Signaling and Androgenesis in the Anovulation of Polycystic Ovary Syndrome

作者：Wu, Xiaoke^*; Wang, Chi Chiu; Cao, Yijuan; Li, Jian; Li, Zhiqiang; Ma, Hongli; Gao, Jingshu; Chang, Hui; Zhang, Duojia; Cong, Jing; Wang, Yu; Wu, Qi; Han, Xiaoxiao; Chung, Pui Wah Jacqueline; Li, Yiran; Zheng, Xu; Chen, Lingxi; Zeng, Lin; Borchert, Astrid; Kuhn, Hartmut; Chen, Zi-Jiang; Ng, Ernest Hung Yu; Stener-Victorin, Elisabet; Zhang, Heping; Legro, Richard S.; Mol, Ben Willem J.; Shi, Yongyong^*

来源：Engineering, 2023, 23: 103-111.

DOI：10.1016/j.eng.2022.08.013

• Polycystic ovary syndrome
• Infertility
• Ovulation responses
• ZNF438
• REC114
• Whole-exome sequencing
• Deep machine learning

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 singlenucleotide 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 Chi 10(-8)) and a rare functional mutation in REC114 (rs182542888, p = 5.79 Chi 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-Mullerian 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. (c) 2022 THE AUTHORS. Published by Elsevier LTD on behalf of Chinese Academy of Engineering and Higher Education Press Limited Company. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

• 单位
  四川大学; 1; 山东大学; 青岛大学; 复旦大学; 上海交通大学; 同济大学; xk; 中国医科大学