Exploring the causal relationship between 91 inflammatory cytokines and two subtypes of rheumatoid arthritis: a bidirectional two-sample Mendelian randomization study

Abstract

Objective In previous studies, the occurrence of rheumatoid arthritis (RA) has been reported to be associated with various inflammatory cytokines. This research aims to investigate the causal relationship between 91 inflammatory cytokines and two distinct subtypes of RA, employing bidirectional two-sample Mendelian Randomization (MR) analysis. Methods Utilizing genetic summary data from a publicly available genome-wide association study (GWAS), we examined the genetic variations of 91 inflammatory cytokines in 14,824 individuals of European ancestry. RA genetic variant data were sourced from the FinnGen consortium, including 4,290 cases and 368,362 controls in the seropositive RA (SPRA) cohort, and 3,877 cases and 285,035 controls in the seronegative RA (SNRA) cohort. Primary analysis employed the Inverse Variance Weighted (IVW) method, with supplementary methods including MR Egger, Weighted Median (WM), Simple Mode, and Weighted Mode to enhance result robustness. Sensitivity analysis was conducted for result reliability. Results IVW analysis revealed elevated levels of natural killer cell receptor 2B4 (CD244), FMS-related tyrosine kinase 3 ligand (FLT3LG), interleukin (IL)-7, and tumor necrosis factor (TNF) significantly associated with an increased risk of SPRA. Lower levels of IL-6 were associated with increased risks of SNRA, while higher levels of IL-7 were related to an increased risk of SNRA. Reverse MR analysis suggested SNRA might downregulate levels of Fractalkine (CX3CL1). Conclusions This study enhances our understanding of the correlation between inflammatory cytokines and RA, providing novel insights into the etiology, diagnosis, and treatment of two RA subtypes.