Mapping the influence of inflammatory cytokines on gout risk: Insights from a comprehensive bidirectional Mendelian randomization analysis

Background The relationship between gout pathogenesis and inflammatory cytokine alterations remains uncertain, with inconsistent findings across studies. This study evaluated the causal links between gout and 41 inflammatory cytokines using Mendelian randomization (MR). Methods Gout-related genetic variants were examined in two large public databases: the Finnish database with 8489 gout patients and 240,862 European ancestry controls and the Genome-Wide Association Studies (GWAS) catalog dataset with 375 gout cases and 455,973 European ancestry controls. Cytokine levels in 8293 healthy participants from the GWAS were analyzed. Moreover, univariate MR analysis, primarily the inverse variance weighting method, was applied to examine the causal association between these factors. The findings were further validated using four additional MR methods based on different modeling assumptions, and their robustness was examined through sensitivity analysis using the MR leave-one-out analysis, Cochran’s Q test, MR-Egger intercept test, and linkage disequilibrium score regression analysis. Results Following Bonferroni correction, this study unveiled a potential connection between macrophage inflammatory protein-1 beta (MIP 1B) and the risk of gout (OR: 1.08, 95%CI: 1.03-1.13, p = 9.61 × 10 -4 ). Additionally, growth-regulated oncogene alpha (GROA) and macrophage migration inhibitory factor (MIF) were implicated in downstream gout development (OR: 1.04, 95%CI: 1.01-1.08, p = 0.02; OR = 1.04, 95%CI: 1.01-1.07, p = 0.0079). Sensitivity analyses confirmed the findings’ reliability and consistency. Conclusion Our study suggests that MIP 1B may be a risk factor for gout, and inflammatory cytokines such as GROA and MIF are involved in the progression of gout. This supports a causal relationship between inflammatory cytokines and gout.