Causal relationship between immune cells, metabolites and polycystic ovary syndrome identified by Mendelian randomization and mediation analyses

Immune cells and blood metabolites play essential roles in the development of polycystic ovary syndrome (PCOS); however, it remains unclear whether blood metabolites mediate the causal relationship between immune cells and PCOS. This study aimed to delineate the causal relationships among immune cells, PCOS and potential blood metabolites through Mendelian randomization (MR). A two-sample MR analysis was conducted using inverse variance weighting as the primary method to determine the causation between immune cells and PCOS risk. This was supplemented by a two-step MR analysis to assess the mediating role of blood metabolites between immune cells and PCOS. In addition, a series of sensitivity analysis methods were employed to test the robustness of the results. We also performed a reverse MR to evaluate the possibility of reverse causal relationships. Our findings identified 22 immune cell phenotypes causally linked to PCOS, with 12 acting as risk factors and 10 as protective factors for PCOS. Furthermore, 45 blood metabolites or ratios were causally related to PCOS. Mediation analysis revealed that X-25519 levels mediated 9.2% of the causal relationship between the absolute count of CD28^-CD25⁺⁺ CD8^br and PCOS. In addition, N-acetylglucosamine/n-acetylgalactosamine levels and adenosine 5'-monophosphate levels mediated 6.7% and -11.1%, respectively, in the causation between naive DN(CD4^- CD8^-) %T cell and PCOS. The aspartate-to-citrate ratio mediated 8.6% of the causal relationship between CD20^- CD38^- %B cells and PCOS. Finally, reverse MR studies did not identify any reverse causation between the 22 immune cell phenotypes and PCOS. This study elucidates the causal links between immune cells and PCOS, highlighting the potential roles of four blood metabolites in mediating the interaction between immune cells and PCOS, thus providing new targets for research and therapeutic interventions.