Background: Polycystic ovary syndrome (PCOS) has a certain genetic predisposition. Previous observational studies have reported alterations in the amino acid profile among women with PCOS, yet causality remains unclear. Our study aims to elucidate the causal relationship through bidirectional Mendelian randomization (MR).

Methods: Leveraging genome-wide association studies (GWAS) data from a European lineage, encompassing 1,400 blood metabolisms, a two-sample MR study was conducted to assess the causal association between PCOS and Leucine. Five models, including inverse variance weighted model (IVW), weighted median estimator model (WME), weighted model-based method (WM), and MR-Egger regression model (MER), estimated causal associations. The leave-one-out sensitivity test, MR-PRESSO, and Cochran’s Q test assessed IVs heterogeneity and pleiotropy.

Results: We found 12 metabolites (8 risk and 3 protective) that showed suggestive associations with PCOS risk. The protective metabolites included Leucine, Isovalerylcarnitine, and hydroxytryptophan. The primary IVW method revealed a negative association between genetically determined PCOS and Leucine levels (OR<0.001, 95%CI: 0.000-0.295, P= 0.018). There was no evidence of pleiotropy by the MR-Egger regression intercept or MR-PRESSO global test (MR-Egger intercept = 0.124, Global test P= 0.637). Multiple metabolic pathways were implicated, including amino acid metabolism and androgen synthesis.

Conclusion: Our MR study underscores a negative correlation between Leucine levels and increased PCOS risk. Identified metabolic products and pathways can serve as biomarkers for clinical screening and prevention, offering insights for future mechanistic exploration and drug target selection. Further observational studies and clinical trials are imperative for comprehensive understanding and validation.

Keywords: Leucine; amino acid; Mendelian randomization; polycystic ovary syndrome; blood metabolism

Disclosure

M. Cai: None. J. Lu: None. D. Dilimulati: None. Y. Zhang: None. H. Chen: None. S. Qu: None. M. Zhang: None.

Funding

National Key R&D Program of China (No.2018YFC1314100); National Nature Science Foundation of China (No. 82170861 and No.81970677); Clinical Research Plan of SHDC (No. SHDC2020CR1017B).

© 2024 by the American Diabetes Association
2024
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