Beyond association: Mediation roles of lipidomics and cytokine in PCOS uncovered by cross-disciplinary genomics.

BACKGROUND AND AIMS: Polycystic ovary syndrome (PCOS) is a metabolic disorder that significantly impacts female fertility. Lipids and inflammation are key factors in the pathogenesis and progression of PCOS. This study aims to elucidate the complex causal relationships involving 179 lipids, 91 inflammatory markers, and PCOS using robust Mendelian Randomization (MR) methods based on Genome-Wide Association Studies (GWAS). Additionally, we seek to quantify the mediating effects of inflammation markers on lipid in PCOS.

METHODS AND

RESULTS

After rigorous screening of eligible SNPs, IVW was employed, supplemented by Simple mode, Weighted median, Weighted mode, and Bayesian Weighted Mendelian Randomization analyses. Sensitivity analyses were performed to ensure result accuracy. Mediation analysis was conducted to identify inflammation factors mediating the lipid-PCOS pathway. We identified 11 lipids causally associated with PCOS, including sterol esters, phosphatidylcholine, sphingomyelin, and triacylglycerol. MR Analysis linked these lipids to 58 inflammatory factors, of which only two were associated with PCOS, with β-NGF increasing the risk of PCOS by 6.50% and uPA reducing it by 4.60%. Mediator analysis showed the effect of uPA-mediated phosphatidylcholine (18:2_20:4) on PCOS.

CONCLUSION

This study is the first to use MR to explore causal links between lipids, inflammatory factors, and PCOS. We identified uPA as a key mediator and uncovered 11 lipids significantly associated with PCOS, highlighting the phosphatidylcholine (18:2_20:4)-uPA-PCOS pathway. Our findings suggest targeting lipid metabolism and using phosphatidylcholine (18:2_20:4) and uPA as biomarkers and tools for evaluating therapeutic efficacy in PCOS.