Investigating the dual causative pathways linking immune cells and venous thromboembolism via Mendelian randomization analysis

Background: Venous thromboembolism (VTE) is a common vascular disease with a significant global burden, influenced by multiple factors, such as genetic, environmental, and immune components. Immune responses and shifts in immune cell profiles are closely linked to the development and progression of VTE, yet current studies are limited by confounding factors and reverse causation. To address these limitations, this study uses Mendelian randomization to explore the causal relationship between immune cell traits and VTE, aiming to provide insights into underlying mechanisms.

Methods: We utilized GWAS data on 731 immunological traits (n = 3757) from the IEU OpenGWAS project and VTE (21021 cases, 391160 controls) from Finngen public data. Five commonly used Mendelian randomization (MR) methods were employed, including inverse-variance weighted (IVW), MR-Egger regression, weighted median estimator (WME), and both weighted and simple models to analyze their associations. Sensitivity checks for the results included pleiotropy tests, heterogeneity tests, and leave-one-out analyses.

Results: From a strictly statistical perspective, no significant associations were observed after FDR correction. However, our exploratory analysis suggested potential trends between immune cell traits and VTE. When immune cells were considered as the exposure and VTE as the outcome, 44 immune cell traits were suggestively associated with VTE based on uncorrected p-values. Conversely, when VTE was considered as the exposure, it appeared to influence immune cell traits. Specifically, secreting CD4 regulatory T cells (OR = 0.9084; 95% CI: 0.8418-0.9804; P = 0.0135; FDR = 0.7339) and activated and resting CD4 regulatory T cells (OR = 0.9275; 95% CI: 0.8622-0.9977; P = 0.0433; FDR = 0.8048) suggested a potential protective trend against VTE. On the other hand, B cells expressing CD20 (OR = 1.0697; 95% CI: 1.0227-1.1188; P = 0.0033; FDR = 0.5767) and myeloid cells expressing CD33 (OR = 1.0199; 95% CI: 1.0021-1.0382; P = 0.0296; FDR = 0.7339) may be linked to an increased risk of VTE.

Conclusions: From a strict statistical perspective, no significant associations were identified after FDR correction. However, our analysis using MR method suggests a potential link between VTE and immune cell traits, suggesting the complex interplay between the immune system and thrombotic events. While this study is exploratory and needs validation, the findings of this study are hypothesis-generating with resect to the mechanisms underlying VTE and encourage further investigation into the role of immune activity in VTE pathology.