Causal Relationship Between Immune Cells and Venous Thromboembolism: A Bidirectional Two-Sample Mendelian Randomization Study

Qiwen Su,1,2 Yue Li,1,2 Cheng Wen,1,2 Lilong Li,1,2 Qianling Ye,2 Ming Chen,2 Linyang Xie,1,2 Chenming Hu,1,2 Huaping Wu1,2 1School of Clinical Medicine, North Sichuan Medical College, Nanchong, People’s Republic of China; 2Department of Vascular Surgery, Dazhou Central Hospital, Dazhou, People’s Republic of ChinaCorrespondence: Huaping Wu, Department of Vascular Surgery, Dazhou Central Hospital, Dazhou, Sichuan, 635000, People’s Republic of China, Email [email protected] Chenming Hu, Department of Vascular Surgery, Dazhou Central Hospital, Dazhou, People’s Republic of China, Email [email protected]: Manny evidence indicates that numerous immune cells are linked to the onset and progression of VTE, though the causal relationship remains unclear. To determine the association between immune cells and VTE, we performed a bidirectional two-sample Mendelian randomization (MR) study.Methods: A comprehensive MR analysis was conducted to ascertain the causal relationship between immune cell signatures and VTE. Leveraging publicly available genetic data, we examined the causal associations between 731 immune cell signatures and the risk of VTE. The analysis encompassed four types of immune signatures, namely median fluorescence intensities, relative cell counts, absolute cell counts, and morphological parameters. We employed the two-sample MR analysis, used the inverse variance-weighted (IVW) approach as the primary analytical method. Rigorous sensitivity analyses were employed to validate the robustness, heterogeneity, and presence of horizontal pleiotropy in the results. Furthermore, the reverse MR analysis was implemented to confirm the existence of reverse causal relationships.Results: Eighteen immune cell signatures were found to have nominally significant associations with VTE according to the IVW method. The level of CD14 expression on CD14+ CD16+ monocytes (OR 0.95) and ten other phenotypes were identified as protective factors against VTE. Conversely, the percentage of HLA DR+ T cells among lymphocytes (OR 1.03) and six other phenotypes were identified as risk factors associated with an increased likelihood of VTE. The expression level of CX3CR1 on CD14- CD16+ monocytes showed a potential bidirectional causal relationship.Conclusion: Our study identified 18 types of immune cell signatures that could impact VTE development, offering novel insights for future mechanistic and clinical studies in this field. Further studies to prospectively validate our findings are needed.Keywords: causal inference, genome-wide association study, immunity, Mendelian randomization analysis, venous thromboembolism