Reciprocal Causal Links in RA Pathogenesis: A Bidirectional MR Study Targeting Th17 Lineage, and CD123-Expressing Dendritic Subsets

Abstract

Objective: Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by persistent joint inflammation and immune dysregulation. Aberrant activation of immune cells plays a central role in RA development and progression. This study aimed to investigate the causal relationships between specific immune cell phenotypes and RA using a bidirectional Mendelian randomization (MR) approach. Methods: We conducted two-sample bidirectional MR analyses using genome-wide association study (GWAS) summary statistics. Genetic variants significantly associated with immune cell traits ([Formula: see text] < 1 × 10[Formula: see text]) were used as instruments for forward MR, while variants associated with RA were selected using a more stringent threshold ([Formula: see text] < 5 × 10[Formula: see text]) for reverse MR in order to enhance the specificity and reliability of causal inference, particularly given the complex genetic architecture of RA. Inverse variance weighted (IVW) analysis served as the primary method, supported by weighted median and MR-Egger regression. Heterogeneity and pleiotropy were assessed using Cochran’s [Formula: see text] test and the MR-Egger intercept. Results: Forward MR identified significant causal associations between RA risk and seven immune traits, including CD4[Formula: see text] T cell memory, CD8[Formula: see text] T cell subsets, dendritic cell (DC) subpopulations, and CD4n:%pre-Th17 cells. In the reverse MR analysis, RA was found to causally affect two immune phenotypes: CD4n:%pre-Th17 and CD123[Formula: see text] on CD11c[Formula: see text] DCs. Conclusions: This study provides genetic evidence supporting a causal interplay between specific immune cell populations and RA. In particular, Th17 precursors and CD123[Formula: see text] DCs emerged as key players in both RA onset and immune remodeling.

Keywords

• Mendelian Randomization
• Rheumatoid Arthritis
• Immune Cells
• Human Immune System Traits