Song Zheng-Qi, Chen Yi-Qi, Yu Tao, Xu Yu-Peng, Chen Yan-Jiong, Lu Xin-Yu, Chen Zhen-Ya, Wang Chen-Yu, Zhang Meng-Ying, Chen Rong, Chen Yi-He
Department of Cardiology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China; The First Clinical Medical College, Wenzhou Medical University, Wenzhou, China.
The Second Clinical Medical College, Wenzhou Medical University, Wenzhou, China.
Heart Lung Circ. 2025 May;34(5):435-443. doi: 10.1016/j.hlc.2024.10.016. Epub 2025 Jan 24.
Regulatory T cells (Tregs) play a crucial role in the development and progression of atherosclerosis. However, the specific association between Treg immune traits and atherosclerosis and related cardiovascular diseases remains unclear, impeding their potential for clinical therapeutic application.
Fifty-eight Treg-related immune traits were obtained from the latest summary level genome-wide association study, which included 3,757 individuals from Sardinia. Additionally, three atherosclerosis subsets and three atherosclerosis-related cardiovascular diseases were obtained from the FinnGen database. Subsequently, comprehensive bidirectional Mendelian randomisation (MR) analysis was performed using inverse-variance weighting as the primary method. Sensitivity analyses were performed to verify the robustness, heterogeneity, and horizontal pleiotropy of the results. Co-localisation analysis was performed to detect whether the exposure and outcome shared causal variants.
Four significant Treg-related immune traits linked to a lower risk of three cardiovascular diseases were identified in the forward MR analysis. Specifically, two traits were identified for cerebral atherosclerosis: CD39 activated CD4 Treg absolute count (OR 0.70, 95% CI 0.57-0.87, p=0.040 [false discovery rate]) and activated CD4 Tregs % CD4 T cells (OR 0.64, 95% CI 0.48-0.84, p=0.040). In addition, CD28 on secreting CD4 Tregs (OR 0.95, 95% CI 0.93-0.98, p=0.014) was detected for other atherosclerosis. In ischaemic heart disease, CD28 on activated CD4 Tregs was protective (OR 0.96, 95% CI 0.95-0.98, p=0.020). An increased intensity of CD3 and CD4 was observed in reverse MR after the occurrence of stroke and ischaemic heart disease, respectively, whereas a lower number and proportion of CD39-secreting CD4 Tregs were noted after ischaemic heart disease. Co-localisation analysis indicated that there were no shared causal variants among significant associations in forward MR.
This study revealed a potential causal relationship between Tregs and atherosclerosis and related cardiovascular diseases, providing a plausible hypothesis for future clinical and basic research.
调节性T细胞（Tregs）在动脉粥样硬化的发生和发展中起关键作用。然而，Treg免疫特征与动脉粥样硬化及相关心血管疾病之间的具体关联仍不明确，这阻碍了它们在临床治疗中的应用潜力。
从最新的汇总水平全基因组关联研究中获取了58个与Treg相关的免疫特征，该研究纳入了来自撒丁岛的3757名个体。此外，从芬兰基因数据库中获取了三个动脉粥样硬化亚组和三种与动脉粥样硬化相关的心血管疾病。随后，以逆方差加权为主要方法进行了全面的双向孟德尔随机化（MR）分析。进行敏感性分析以验证结果的稳健性、异质性和水平多效性。进行共定位分析以检测暴露因素和结局是否共享因果变异。
在前向MR分析中，确定了四个与三种心血管疾病风险降低相关的重要Treg相关免疫特征。具体而言，确定了两个与脑动脉粥样硬化相关的特征：CD39激活的CD4 Treg绝对计数（比值比0.70，95%置信区间0.57 - 0.87，p = 0.040[错误发现率]）和激活的CD4 Tregs占CD4 T细胞的百分比（比值比0.64，95%置信区间0.48 - 0.84，p = 0.040）。此外，对于其他动脉粥样硬化，检测到分泌CD4 Tregs上的CD28（比值比0.95，95%置信区间0.93 - 0.98，p = 0.014）。在缺血性心脏病中，激活的CD4 Tregs上的CD28具有保护作用（比值比0.96，95%置信区间0.95 - 0.98，p = 0.020）。在中风和缺血性心脏病发生后，分别在反向MR中观察到CD3和CD4强度增加，而在缺血性心脏病后，分泌CD39的CD4 Tregs数量和比例较低。共定位分析表明，在前向MR的显著关联中没有共享的因果变异。
本研究揭示了Tregs与动脉粥样硬化及相关心血管疾病之间的潜在因果关系，为未来的临床和基础研究提供了一个合理的假设。
