Mendelian randomization analysis of immune cell subsets and inflammatory cytokines in aplastic anaemia

Aplastic anemia (AA) is an immune-mediated bone marrow failure syndrome marked by pancytopenia and depletion of hematopoietic stem cells. Although autoreactive T cells and inflammatory cytokines are involved in its pathogenesis, their causal relationships remain unclear. We conducted a bidirectional two-sample Mendelian randomization using large-scale genome-wide association study datasets to explore the causal roles of 731 immune cell traits and 91 inflammatory cytokines in AA. The primary analysis used inverse-variance weighting, with additional sensitivity analyses including MR-Egger regression and MR-PRESSO. Mediation analysis was performed to determine whether cytokines mediate the effects of immune cells on disease risk. We identified 12 immune cell traits conferring protection against aplastic anemia (AA). The strongest protective association was observed for TD CD4 + AC (OR = 0.890, 95% CI: 0.817-0.968, P = 0.007). Conversely, 24 immune cell traits demonstrated positive associations with increased AA risk, with the strongest association found for CD127 - CD8br %T cell (OR = 1.135, 95% CI: 1.032-1.247, P = 0.009). Elevated levels of leukemia inhibitory factor (LIF) and its receptor were associated with reduced AA risk. Mediation analysis indicated partial mediation by LIF of the associations linking dendritic cells, HLA-DR + + monocytes, and AA risk. Sensitivity analyses supported the robustness of these findings. This study established causal relationships between specific immune cell phenotypes, inflammatory cytokines, and AA. Importantly, LIF partially mediated the effects of immune cells on AA, suggesting the LIF-LIFR axis as a potential therapeutic target.