Bidirectional Mendelian randomization reveals causal immune cell phenotypes in rheumatoid arthritis

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by persistent inflammation in synovial joints and influenced by genetic and environmental factors. The immune system, comprising various cells that either exacerbate or reduce inflammation, plays a central role in RA pathogenesis. Despite extensive research, the causal relationships between immune cell phenotypes and RA remain unclear. We employed a two-sample Mendelian randomization (MR) approach to investigate the causal associations between 731 immune cell phenotypes and RA. Genetic variants, carefully selected based on rigorous criteria, served as instrumental variables to ensure analytical validity. Data on RA were derived from the FinnGen database, whereas immune cell phenotype data were obtained from the genome-wide association studies catalog. We employed 5 MR methods, including inverse variance weighted and MR Egger, to ensure robust causal inference. We assessed for pleiotropy and heterogeneity and adjusted findings using the False Discovery Rate. After False Discovery Rate adjustment (threshold < 0.05), inverse variance weighted analysis revealed potential causal relationships between 4 immune cell types and RA: CD62L- dendritic cells %dendritic cells (P = 3.88E-05; 95% confidence interval [CI] = 1.056), CD19 on IgD+ CD38- naive cells (P = 1.75E-04; 95% CI = 0.969), CD45RA on TD CD8br (P = 5.59E-04; 95% CI = 0.919), and HLA DR on CD33- HLA DR+ (P = 8.13E-05; 95% CI = 1.422). In reverse Mendelian studies, specific immune cell phenotypes were found to be associated with RA risk and progression: the percentage of memory B cells among lymphocytes (P = 2.74E-04; 95% CI = 0.861), IgD+ CD24+ cells among lymphocytes (P = 6.93E-04; 95% CI = 0.867), CD4+ CD8dim cells among lymphocytes (P = 2.92E-04; 95% CI = 0.802), CD4+ CD8dim cells among leukocytes (P = 4.37E-04; 95% CI = 0.814), and CD24 expression on IgD+CD24+ cells (P = 1.05E-04; 95% CI = 0.857). These results identify immune cell phenotypes closely linked to RA susceptibility and progression. The findings suggest that specific immune cell phenotypes are not only influenced by RA but may also contribute to its development and progression. These results offer new insights into the immunological underpinnings of RA and highlight potential targets for therapeutic intervention. Future research should focus on validating these causal relationships in diverse populations and exploring the molecular mechanisms involved.