Qi Ning, Lyu Zhuochen, Huang Lu, Zhao Yun, Zhang Wan, Zhou Xinfeng, Zhang Yang, Cui Jiasen
Department of Vascular Surgery, Huadong Hospital, Fudan University, Shanghai, 200040, China.
Shanghai Key Laboratory of Clinical Geriatric Medicine, Huadong Hospital, Fudan University, Shanghai, 200040, China.
Thromb J. 2025 Jan 23;23(1):8. doi: 10.1186/s12959-025-00692-1.
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.
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.
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.
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.
静脉血栓栓塞症（VTE）是一种常见的血管疾病，在全球范围内负担沉重，受多种因素影响，如遗传、环境和免疫因素。免疫反应和免疫细胞谱的变化与VTE的发生和发展密切相关，但目前的研究受到混杂因素和反向因果关系的限制。为解决这些局限性，本研究采用孟德尔随机化方法来探索免疫细胞特征与VTE之间的因果关系，旨在深入了解潜在机制。
我们利用了来自IEU OpenGWAS项目的731个免疫性状（n = 3757）的全基因组关联研究（GWAS）数据以及来自芬兰基因公共数据的VTE（21021例病例，391160例对照）数据。采用了五种常用的孟德尔随机化（MR）方法，包括逆方差加权法（IVW）、MR-Egger回归、加权中位数估计法（WME）以及加权和简单模型来分析它们之间的关联。对结果的敏感性检验包括多效性检验、异质性检验和留一法分析。
从严格的统计学角度来看，经错误发现率（FDR）校正后未观察到显著关联。然而，我们的探索性分析表明免疫细胞特征与VTE之间存在潜在趋势。当将免疫细胞视为暴露因素，VTE视为结局时，基于未校正的p值，44个免疫细胞特征与VTE存在提示性关联。相反，当将VTE视为暴露因素时，它似乎会影响免疫细胞特征。具体而言，分泌型CD4调节性T细胞（比值比[OR] = 0.9084；95%置信区间[CI]：0.8418 - 0.9804；P = 0.0135；FDR = 0.7339）以及活化和静息的CD4调节性T细胞（OR = 0.9275；95% CI：0.8622 - 0.9977；P = 0.0433；FDR = 0.8048）显示出对VTE的潜在保护趋势。另一方面，表达CD20的B细胞（OR = 1.0697；95% CI：1.0227 - 1.1188；P = 0.0033；FDR = 0.5767）和表达CD33的髓样细胞（OR = 1.0199；95% CI：1.0021 - 1.0382；P = 0.0296；FDR = 0.7339）可能与VTE风险增加有关。
从严格的统计学角度来看，经FDR校正后未发现显著关联。然而，我们使用MR方法的分析表明VTE与免疫细胞特征之间存在潜在联系，提示免疫系统与血栓形成事件之间存在复杂的相互作用。虽然本研究具有探索性且需要验证，但本研究结果针对VTE的潜在机制提出了假设，并鼓励进一步研究免疫活动在VTE病理过程中的作用。
