Causal associations between systemic inflammation and polycystic ovary syndrome: a Mendelian randomisation study emphasising the role of CXCL11

Purpose Systemic inflammation has been increasingly implicated in the pathogenesis of polycystic ovary syndrome (PCOS), but the causal nature and direction of this relationship remain uncertain. This study aimed to evaluate the potential causal associations between circulating inflammatory cytokines and the risk of PCOS using a Mendelian randomisation (MR) approach. Methods We conducted a two-sample MR analysis using summary-level data from large-scale genome-wide association studies involving 91 systemic inflammatory markers (n=14 824) and PCOS (10 074 cases and 103 164 controls) among individuals of European ancestry. Genetic variants associated with cytokines at genome-wide significance (p<5×10 −8 ) were selected as instrumental variables. The inverse-variance weighted method was used as the primary analytical strategy, supplemented by sensitivity analyses and correction for multiple testing. Results Genetically predicted higher circulating levels of C-X-C motif chemokine ligand 11 (CXCL11) were significantly associated with a reduced risk of PCOS (OR=0.740, 95% CI 0.625 to 0.871, p<0.001), and this association remained statistically significant after multiple testing correction (adjusted p=0.030). Nominal associations with decreased PCOS risk were also observed for interleukin-13 (IL-13), IL-10 and adenosine deaminase (ADA), but these did not withstand correction for multiple comparisons. No evidence of horizontal pleiotropy was detected, and leave-one-out sensitivity analyses supported the robustness of the findings. Conclusion These results support a potential causal role of systemic inflammation in the development of PCOS, with CXCL11 emerging as a promising inflammatory marker and potential therapeutic target. Further studies are needed to validate these findings and explore their clinical relevance in PCOS management.