Genetically predicted inflammatory cytokines mediate the associations between the gut microbiota and ovarian cancer: a bidirectional two-sample Mendelian randomization study

BACKGROUND: Ovarian cancer (OC), the deadliest gynecologic malignancy, lacks effective strategies for early detection and treatment. Emerging evidence suggests that the gut microbiota and inflammatory cytokines may influence OC pathogenesis, but the causal mechanisms remain unclear. This study employed a bidirectional, two-sample Mendelian randomization (MR) analysis with genetic mediation analysis to investigate whether genetically predicted inflammatory cytokines mediate the associations between the gut microbiota and OC. METHODS: This study was based on an analysis of public genetic summary statistics from predominantly European populations. The data from a genome-wide association study (GWAS) and public databases included 473 gut microbiotas (FinnGen, n = 5,959), 91 inflammatory cytokines (GWAS, n = 14,824), and 1,218 OC cases (UK Biobank). Inverse-variance weighted (IVW) was the primary MR method, supplemented by multiple methods such as MR-Egger and other sensitivity analyses to evaluate the robustness of findings. Single-nucleotide polymorphisms (SNPs) associated with exposure were selected as instrumental variables (IVs). Mediation analysis was conducted to explore the potential mediation effect of inflammatory cytokines. RESULTS: Our analysis identified 19 gut microbiotas (9 risk, 10 protective) and 5 inflammatory cytokines (4 risk, 1 protective) with associations suggestive of causality with OC under MR assumptions (PFDR