Two-Sample Bidirectional Mendelian Randomization Analysis of the Causal Relationship Between Immune Cell Phenotypes and Systemic Lupus Erythematosus.

Background: Systemic lupus erythematosus (SLE) is a complex autoimmune disease. Numerous studies suggest that immune cells play a critical role in the onset and progression of SLE; however, the causal mechanisms underlying these associations remain inadequately defined. This study aimed to systematically evaluate, at the genetic level, the potential causal relationships between 731 immune cell phenotypes and SLE using Mendelian randomization (MR), in order to identify potential pathogenic or protective immune biomarkers. Methods: We utilized summary statistics from genome-wide association studies (GWAS) involving 3757 individuals of European Sardinian ancestry for 731 immune cell phenotypes and a GWAS for SLE comprising 647 cases and 482,264 controls of European ancestry. Single nucleotide polymorphisms (SNPs) significantly associated with immune phenotypes were selected as instrumental variables. The inverse variance weighted (IVW) method was employed as the primary MR analysis, complemented by the weighted median method, MR-Egger regression, simple mode method, and weighted mode method for validation. Sensitivity analyses included Cochran's Q test, MR-Egger intercept test, MR-PRESSO global test, and leave-one-out analysis to assess heterogeneity, horizontal pleiotropy, and robustness. In addition, reverse MR analysis was conducted to explore the potential causal effects of SLE on immune cell phenotypes. Results: A total of 24 immune cell phenotypes were identified to have significant causal associations with SLE, of which six showed positive correlations and eighteen showed negative correlations. These associations primarily involved key immune molecules including HLA-DR, CD25, CD45/CD45RA, CD8, BAFF-R, CD24, CD14, CX3CR1, CD28, CD11b, CD4, CD3, CD27, and CD16. Reverse MR analysis revealed that only IgD⁺ CD24 Conclusion: The findings suggest that immune cell phenotypes may contribute to SLE pathogenesis through mechanisms including immune tolerance regulation, self-antigen recognition, and inflammation amplification. Several phenotypes significantly associated with SLE, such as HLA-DR, CD3, CD24, CD25, CX3CR1, CD8, remain insufficiently investigated at the mechanistic level and may serve as promising targets for future basic and clinical research, with potential therapeutic implications and translational value.