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 _FDR =0.040 [false discovery rate]) and activated CD4 Tregs % CD4 ⁺ T cells (OR 0.64, 95% CI 0.48–0.84, p _FDR =0.040). In addition, CD28 on secreting CD4 Tregs (OR 0.95, 95% CI 0.93–0.98, p _FDR =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 _FDR =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.