The Association Between Immune Cells and Venous Thromboembolism: A Causal Inference Based on Mendelian Randomization.

BackgroundEmerging evidence suggests that various types of immune cells are associated with venous thromboembolism (VTE). However, the roles of distinct immune cell phenotypes in VTE remain largely unclear.MethodsBy analyzing 731 distinct immune traits identified through genome-wide association studies (GWAS) and publicly available genetic data from patients with VTE in the FinnGen database, we applied rigorous quality control steps to identify instrumental variables (IVs) associated with exposure. We performed two-sample Mendelian randomization (MR) using inverse-variance weighting to assess causal associations between 731 immune traits and VTE, including deep vein thrombosis (DVT) and pulmonary embolism (PE). To assess the robustness of the findings, sensitivity analyses such as leave-one-out cross-validation and additional Mendelian randomization approaches were performed. Subsequently, Bayesian colocalization analysis (COLOC) was employed to identify potential colocalized genetic signals, thereby providing additional support for the MR findings.ResultsAt an FDR-adjusted significance threshold, three immune phenotypes, including CD4 on CD39+CD4+T cell, naive CD4+ T cell absolute cell counts (ACs), and CD4-CD8-natural killer (NK) T% T cell were negatively associated with the risk of VTE. CD45RA+ CD8+ T cell AC was negatively linked to the onset of DVT. Additionally, five immune phenotypes, including human leukocyte antigen (HLA) DR+ NK%CD3-lymphocyte, HLA DR+ NK%NK, side scatter area (SSC)-A on HLA DR+ NK, PDL-1 on CD14-CD16+ monocyte and CD16 on CD14+CD16+ monocyte were negatively associated with the risk of PE. CD86+ myeloid dendritic cell (DC) ACs and CD86+ myeloid DC% DC were positively correlated with PE. COLOC analysis revealed that naive CD4+ T cell AC variants (rs3104369) colocalized with VTE.ConclusionOur findings reveal that different immune phenotypes exhibit either protective or risk-increasing effects on VTE, improving our understanding of VTE risk factors and offering valuable insights for advancing future research and clinical implementation.