The causal relationship between immune cells and both seropositive and seronegative rheumatoid arthritis: A bidirectional Mendelian randomization study

Rheumatoid arthritis (RA) is a chronic, immune-mediated disease with symmetric polyarticular pain and swelling. It includes seropositive RA, marked by specific antibodies, and seronegative RA, without these antibodies. The relationship between immune cells and both types of RA has not been fully elucidated. Therefore, we conducted a two-sample Mendelian randomization analysis with bidirection to evaluate the causal relationship between immune cells and both seropositive and seronegative RA. We utilized data from various genome-wide association studies and employed multiple analytical methods, including inverse-variance weighted and Wald ratio, as the primary method. Additionally, we employed supplementary approaches such as MR-Egger regression, weighted median, and weighted mode. Various sensitivity analyses were used to ensure the robustness of our results. Furthermore, we utilized the false discovery rate method to mitigate type 1 error. We identified 3 immune cell types linked to higher seropositive RA risk, and 16 immune cell types might be influenced by seronegative RA (4 increased and 12 decreased). Notably, HLA-DR+ monocytes were strongly associated with seropositive RA, while changes in immune cell composition in seronegative RA suggest potential biomarkers for its diagnosis. These findings offer valuable insights into RA pathogenesis and highlight the potential for novel diagnostic and therapeutic strategies, particularly for seronegative RA, which lacks reliable biomarkers. Further research is needed to explore the underlying mechanisms and their clinical applications.