Exploration of causal relationship between transplant rejection and immune cells: A two-sample Mendelian randomization study

Post-transplant rejection is a serious problem for patients undergoing organ transplantation. It is currently believed that immune-related factors are the main causes of transplant rejection, but the roles of many immune cell phenotypes are still unclear. We utilized Mendelian randomization analysis to explore the association between 731 immune cell and the risk of transplant rejection. We systematically analyzed 731 immune cell phenotypes (including absolute counts, surface markers, and functional states) from peripheral blood of 3657 European individuals. Genetic instruments were selected at a genome-wide significance threshold (p < 1 × 10⁻⁵) to assess bidirectional causal relationships with transplant rejection events from FinnGen biobank (n = 16,380,395 SNPs). Forward MR analysis identified 33 immune phenotypes significantly associated with rejection risk: 19 protective (odds ratio [OR] < 1, p < 0.05) predominantly in B cell subsets, and 14 risk-enhancing phenotypes (OR > 1). Reverse MR revealed that rejection events causally altered 34 immune phenotypes, upregulated 18 effector phenotypes and downregulated 16 regulatory phenotypes. Sensitivity analyses confirmed robustness against pleiotropy (MR-Egger intercept p > 0.05, MR-PRESSO global test p > 0.01 and heterogeneity test p > 0.05). These findings highlight the dynamic interplay between B cell plasticity and Treg depletion in transplant outcomes, suggesting novel therapeutic targets for rejection prevention. Our research confirms the close relationship between transplant rejection and immune cells, especially that certain B cell subsets are causally linked to a lower risk of transplant rejection, providing new targets and insights for future clinical treatments.