Uncovering Causal Associations of Immune Cells with Rheumatoid Arthritis: A Mendelian Randomization Study

Abstract

Abstract Background Rheumatoid arthritis (RA) is a chronic autoimmune disorder characterized by progressive joint damage and functional limitations, often accompanied by comorbidities. While the impact of immune cells on the development of RA is recognized, the precise causal relationships with various immunophenotypes are yet to be fully understood. Methods We performed a comprehensive two-sample Mendelian randomization (MR) study to explore the associations between immunophenotypes and RA. Utilizing publicly available genetic datasets, we examined causal links involving 731 immune cell traits, categorized into four groups: relative cell counts (RC), median fluorescence intensities (MFI), morphological parameters (MP), and absolute cell counts (AC). Extensive sensitivity analyses were carried out to validate the robustness of our results. These analyses aimed to assess heterogeneity and investigate the potential influence of horizontal pleiotropy. Results After applying FDR correction, two specific immunophenotypes were found to be associated with RA: CD33dim HLA-DR + CD11b+ %CD33dim HLA-DR + and CD33dimHLA-DR + CD11b-%CD33dimHLA-DR+. The odds ratios (ORs) for RA risk forthese immunophenotypes, calculated using the inverse variance weighting(IVW) method, were 0.970 (95% CI = 0.955–0.985, P = 1.09×10− 4, PFDR = 0.058) and 1.027 (95% CI = 1.011–1.042, P = 5.05×10− 4, PFDR = 0.074), respectively. In contrast, without FDR correction, six additional immunophenotypes showed significant associations with RA: CD14 on CD33dim HLA-DR + CD11b+, CD16 on CD14 + CD16 + monocytes, CD11b on basophils, CD3 on TD CD4+, PDL-1 on CD14- CD16 + monocytes, and CD4 on HLA-DR + CD4+. Of these, the first two were linked to increased RA risk, while the latter four exhibited protective characteristics. Conclusions This study highlights a strong genetic link between immune cell profiles and RA, illuminating potential targets for innovative therapeutic strategies.