Immune cell of CD127 on CD28+ CD45RA+ CD8br-Regulated ZDHHC20 Prevents the Progression of Atrial Fibrillation

Background Protein palmitoylation is involved in various biological processes and has been implicated in the pathogenesis of atrial fibrillation (AF). Given the emerging evidence suggesting a role of immune cells in AF, it is plausible that palmitoylation may influence AF susceptibility through immune-mediated mechanisms. This study aimed to investigate the causal relationship and underlying mechanisms among palmitoylation-related genes, immune cell subsets, and AF using Mendelian randomization (MR) approaches. Methods and Results This study employed two-sample MR, summary-data-based MR (SMR), and mediation analyses. Genetic association data were obtained from the Finngen consortium for AF, the eQTL consortium for palmitoylation-related genes, and the GWAS Catalog for immune cell traits. First, a two-sample MR was used to assess the causal relationship between palmitoylation-related genes and AF risk. SMR analysis was subsequently performed to examine the association between gene expression and AF. Finally, mediation analysis was conducted to evaluate the role of immune cells in mediating the relationship between gene expression and AF risk. The results demonstrated that higher expression of ZDHHC20 was significantly associated with a reduced risk of AF [OR = 0.9244 (95% CI:0.8774–0.9739), p = 0.003]. Further mediation analysis revealed that ZDHHC20 positively regulates CD127 on CD28 + CD45RA+ CD8br (Treg), which in turn indirectly modulates AF risk, with a mediation proportion of 15.65%. Conclusions This study employed two-sample MR, SMR, and mediation analysis to elucidate a significant association between ZDHHC20 expression and AF risk, mediated by CD127 on CD28 + CD45RA+ CD8br (Treg). These findings provide novel insights into the pathophysiology of AF and highlight the critical role of epigenetic regulation in cardiovascular disease.