Yifei Zhang, Wuxiao Yang, Xuewen Li
Background: Pericarditis is an inflammatory heart disease with unclear causal mechanisms. Immune dysregulation is implicated, but observational studies cannot reliably infer causality. Whether plasma metabolites mediate immune-pericarditis pathways remains unknown. Methods: A two-sample Mendelian randomization (MR) study was performed using publicly available summary-level genome-wide association study data. Genetic instruments were selected via significance screening, linkage disequilibrium clumping, and strength evaluation (F-statistic > 10). A relaxed instrument selection threshold of p < 1 × 10-5 was used for immunophenotypes and metabolites, and a threshold of p < 5 × 10-6 was applied for pericarditis in reverse MR. Forward MR assessed potential causal effects of immune cells and metabolites on pericarditis; reverse MR tested the opposite direction. Two-step mediation MR evaluated whether metabolites mediated immune-to-pericarditis pathways. The primary method was inverse variance weighting (IVW), complemented by a range of sensitivity analyses. Results: A total of 18,621 SNPs served as instruments for immunophenotypes and 34,843 for metabolites. Forward MR identified 29 immunophenotypes with genetically predicted associations with pericarditis (20 risk, 9 protective). Reverse MR identified 13 immunophenotypes associated with genetic susceptibility to pericarditis, indicating a bidirectional genetic architecture. Ten plasma metabolites showed genetically predicted associations with pericarditis. After false discovery rate (FDR) correction, these key associations remained significant. Mediation analysis identified a putative immunometabolic pathway in which CD25 on IgD+ CD38br B cells increased pericarditis risk partly through downregulation of the protective metabolite cholate (β1 = -0.114, p = 0.002; β2 = -0.419, p = 0.001). The indirect effect was 0.048 (95% CI: 0.012 to 0.097), accounting for 32.8% of the total effect. All key results were robust in sensitivity analyses. Conclusions: This study provides genetic evidence supporting a putative immune cell-metabolite-pericarditis pathway involving CD25-positive B cells and cholate, and suggests potential immunometabolic targets for future investigation.