Causal Relationship Between Inflammatory Cytokines and Polycystic Ovary Syndrome: A Bidirectional Mendelian Randomization Study

Abstract Polycystic ovary syndrome (PCOS) is defined as a chronic low-grade inflammatory reproductive endocrine disorder. PCOS can induce various metabolic disorders, which are associated with a state of mild and slow-acting inflammation. Nevertheless,it‘s uncertain that the causation about PCOS and inflammatory factors. The causality between inflammatory cytokines and PCOS was analyzed by bidirectional Mendelian randomization (MR) in this current probe. We performed an interactive MR study to assess the causal relationships between 91 inflammatory cytokines and PCOS using Genome Wide Association Study (GWAS) data. We underwent dual-sample MR analysis with inverse variance weights (IVW) as the predominant MR methodology with multiple validity and heterogeneity analyses. MR-Egger, weighted median, simple mode, weighted mode and MR-PRESSO were analyzed as multiple likelihood sensitivity analyses to enhance the final results.The results came out interleukin-1-alpha (IL-1A) levels (odds ratio OR = 1.051, 95% fiducial interval 95% CI = 1.009–1.095, P = 0.02) and oncostatin-M (OSM) levels ( OR = 1.041, 95% CI = 1.001–1.082, P = 0.04) were positively associated with the development of PCOS. Moreover, interleukin-7 (IL-7) levels (OR = 0.935, 95% CI = 0.884–0.989, P = 0.02); interleukin-15 receptor subunit alpha (IL15RA) levels (OR = 0.959, 95% CI = 0.929–0.99, P = 0.01); and C-X-C motif chemokine 11 (CXCL11) levels (OR = 0.959, 95% CI = 0.922–0.996. P = 0.03) were strongly negatively associated with PCOS. However, we did not find any strong positive results in the reverse analysis, suggesting that although inflammatory factors contribute to the pathogenesis of PCOS, PCOS itself does not trigger inflammatory factor production.Our study provides genetic evidence for the connection between systemic inflammatory regulators and PCOS. Treatments targeting specific inflammatory factors may help to mitigate the risk of PCOS. The levels of five of the 91 inflammatory factors included in this study, namely, IL1A and OSM, were associated with PCOS. IL1A and OSM contribute to the progression of PCOS while IL-7, IL15RA, and CXCL11 levels are negatively correlated with the development of PCOS.