Assessing the causal relationship between immune cells and rheumatoid arthritis: a bi-directional Mendelian randomization (MR) study.

Background: Rheumatoid Arthritis (RA) is a chronic and refractory autoimmune disease that mostly affects the joints of the hands and feet. Existing objective studies show that inflammatory and immunological factors are important in the development of RA. However, the complex causal relationship between immune cells and RA is unclear.

In this study, we aimed to elucidate the potential causal effects of immune cell subsets on RA risk using genetic instruments derived from genome-wide association studies (GWAS) of immune cell traits and RA. Additionally, we conducted reverse MR analyses to explore the impact of RA on immune cell levels, providing a comprehensive understanding of the bidirectional relationships between immune cells and RA. The research aims to provide a novel scientific view for the prevention and targeted treatment of RA.

We conducted a bi-directional two-sample Mendelian randomization(MR) analysis using publicly available large-scale genetic data of 731 immune cells and RA to uncover the potential causal relationship. The MR analyses employed the inverse variance-weighted (IVW) or Wald ratio method as the primary tool, supplemented by MR-Egger, weighted median, and weighted mode methods to enhance reliability and address potential heterogeneity and horizontal pleiotropy.

After Bonferroni correcting, we observed that increased levels of two immune phenotypes were causally associated with RA risk, that were CD62-CD86+ myeloid Dendritic Cell Absolute Count (odds ratio(OR)=1.085, p=5.23E-05) and CD127- CD8+ T cell Absolute Count (OR=1.376, 95% CI:1.234–1.530, p=4.22E-09). 5 immune cell characteristics demonstrated protective effects against RA, including CD3 on CD39+ resting CD4 regulatory T cell (OR=0.817, p=4.22E-09), CD3 on CD28- CD8+ T cell (OR=0.735, p=2.56E-07), HVEM on naive CD8+ T cell (OR=0.825, p = 6.42E-06), HVEM on Central Memory CD4+ T cell (OR=0.847, p=1.84E-06), HVEM on Central Memory CD8+ T cell (OR=0.867, p=5.97E-06). We founded that the affected 4 immune cells by RA were mainly concentrated in B cells.

The study reveals a noteworthy association between RA and various immune cells, providing valuable insights for clinical research and aiding the advancement of immunologically-based therapeutic strategies.