Abstract
BACKGROUND: An imbalance of innate and acquired immune responses is significantly involved in the pathophysiology of coronary atherosclerosis and the occurrence of ischemic heart disease (IHD). Regulatory T cells (Tregs) play an essential regulatory role in atherosclerotic plaque formation and maintenance; therefore, dysfunction of Tregs triggers the formation of atherosclerotic plaques and accelerates their progression. However, due to the inherent limitations of observational research, clinical evidence is limited concerning the relationship between the variation in peripheral Tregs and the risk of IHD, and the cause-and-effect relationship between these factors is unclear. Mendelian randomization (MR) uses genetic variation as a proxy for exposure and can be used to inferentially determine the causal effect of exposure on outcomes. We thus used MR analysis to investigate whether there is a causal relationship between the biomarkers of Tregs and IHD. METHODS: Selected genetic variants (P<5.00E-08) from the summary data of a genome-wide association study (GWAS) were used to conduct a two-sample bidirectional MR analysis. The analysis included 51 extensive Treg subtypes involving 3,757 individuals from the general population. Summary statistics of IHD were obtained from the IEU open GWAS project, which contains 30,952 cases and 187,845 controls. The populations in both GWAS studies were of European ancestry. RESULTS: We identified a set of 197 single-nucleotide polymorphisms (SNPs) that served as instrumental variables (IVs) for evaluating 51 Treg subtypes. Thirteen significant variables were found to be potentially associated with IHD. After false-discovery rate (FDR) adjustment, we identified four Treg subtypes to be causally protective for IHD risk: CD28 on activated & secreting CD4 Tregs [odds ratio (OR) =0.89; 95% confidence interval (CI): 0.82-0.96; P=3.10E-03; adjusted P=0.04], CD28 on activated CD4 Tregs (OR =0.87; 95% CI: 0.80-0.95; P=3.10E-03; adjusted P=0.04), CD28 on CD4 Tregs (OR =0.87; 95% CI: 0.80-0.96; P=3.41E-03; adjusted P=0.04), and CD28 on resting CD4 Treg cell (OR =0.91; 95% CI: 0.85-0.97; P=3.48E-03; adjusted P=0.04). Reverse MR analysis found eight potential causal variables, but these associations were nonsignificant after FDR correction (all adjusted P values >0.05). CONCLUSIONS: This study identified the significance of elevated CD28 expression on CD4 Tregs as a novel molecular modifier that may influence IHD occurrence, suggesting that targeting CD28 expression on CD4 Tregs could offer a promising therapeutic approach for IHD.