Dissecting immune-mediated pathways in rheumatoid arthritis: A multivariate mediation analysis of antibodies and circulating proteins

Rheumatoid arthritis (RA) is a chronic inflammatory disorder with complex etiologies involving immune responses and circulating proteins. This study investigates the causal relationships between antibody immune responses, plasma circulating proteins, and the development of RA using Mendelian Randomization (MR) analysis; A two-sample and multivariate MR analysis was conducted to explore the mediating causal relationship between 46 antibody immune responses and RA through 4,907 plasma circulating proteins. Genetic variations were utilized as instrumental variables (IVs) to infer causality, ensuring that they met the assumptions of relevance, independence, and exclusion restriction. Data were sourced from the FinnGen R10 dataset, UK Biobank, and the SomaScan platform, providing a robust foundation for the analysis. Statistical methods including IVW, weighted median, and mode-based approaches were employed, complemented by sensitivity analyses to ensure the robustness of the findings; The study identified significant causal relationships between six antibody immune responses and RA, with three specific responses—Epstein-Barr virus EBNA-1, Epstein-Barr virus ZEBRA, and Anti-polyomavirus 2 IgG seropositivity—showing strong associations. However, reverse causality was detected for EBNA-1 and ZEBRA, leading to their exclusion from further analysis. Additionally, 12 plasma circulating proteins were found to have significant causal relationships with RA, with KCNIP3 emerging as a key protective factor. Multivariate MR analysis revealed that KCNIP3 mediates the relationship between Anti-polyomavirus 2 IgG seropositivity and RA, suggesting a potential protective mechanism. This study highlights the intricate relationships between specific antibody responses, circulating proteins, and RA risk. The findings suggest that certain proteins, particularly KCNIP3, may mediate the effects of immune responses on RA development, offering potential targets for therapeutic intervention.