Inflammatory cytokines, metabolites, and rheumatoid arthritis

Background: Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by persistent inflammation and joint destruction. Although the roles of inflammatory cytokines and metabolites in RA pathogenesis have caught a lot of attention, there is a lack of systematic studies, and their causal relationships remain unclear. Methods: We conducted a two-step mendelian randomization analysis utilizing genetic data from genome-wide association studies (GWAS) of inflammatory cytokines, metabolites, and RA. The first step assessed the causal effect of 91 inflammatory cytokines and 1400 metabolites on RA risk using inverse variance weighted method, complemented by MR-Egger, weighted median, simple mode and MR-PRESSO to ensure robustness and assess pleiotropy. The second step evaluated the mediation effects of selected metabolites on the relationship between cytokines and RA. Results: The analysis identified 9 inflammatory cytokines, including IL-1 alpha and IL-10, which significantly increase RA risk, while TNF-beta exhibited a protective effect. Additionally, 6 metabolites were associated with increased RA risk, including 1-(1-enyl-palmitoyl)-2-arachidonoyl-GPE and arachidonate (20:4n6). Conversely, 5 metabolites, such as docosatrienoate (22:3n3) and Cholesterol, were found to reduce RA risk. The mediation analysis revealed that TNF-beta may exerts its protective effect through its influence on specific metabolites, and X-24949, which accounted for a -2.58% mediated effect in the TNF-beta-RA causal pathway. Conclusion: This study explores the complex interplay between inflammatory cytokines, metabolites, and RA. The findings suggest potential biomarkers for early diagnosis and novel therapeutic targets, particularly those related to lipid metabolites and specific cytokines like TNF-beta.