The causal relationship between 91 inflammatory cytokines and chronic pancreatitis, and the mediating role of 1400 metabolites

Considerable amounts of studies have confirmed a close relationship between specific inflammatory cytokines and chronic pancreatitis (CP), while the causal effect between the 2 remains unclear. This study is to evaluate the causal relationship between 91 inflammatory cytokines and CP using bidirectional 2-sample Mendelian randomization (MR) method, and to investigate the mediating role of 1400 metabolites through a 2-step MR analysis. Genome wide association study (GWAS) data related to 91 inflammatory cytokines were sourced from 14,824 participants of European populations, and CP related GWAS data from a Finnish database, covering 3875 cases of CP cases and 361,641 controls. A total of 1400 circulating metabolites were derived from 8299 individuals. This study used inverse variance weighted (IVW) as the main analysis method, complemented by 4 other methods. In addition, sensitivity analysis was conducted at different levels, including Cochran Q statistics, MR-egger intercept, MR-PRESSO global test, and "leave-one-out method" (LOO) analysis, ensuring the robustness of the results. The IVW method revealed that levels of CCL23 [OR = 1.120, 95% CI: 1.014-1.237, P = .026], DNER [OR = 1.151, 95% CI: 1.020-1.300, P = .023], IL-6 [OR = 1.240, 95% CI: 1.034-1.486, P = .020], and TNFRSF9 [OR = 1.156, 95% CI: 1.020-1.309, P = .023] increased the CP risk; while CCL19 [OR = 0.902, 95% CI: 0.820-0.991, P = .033], IFN-gamma (IFN-γ) [OR = 0.847, 95% CI: 0.734-0.977, P = .023], IL-10 [OR = 0.853, 95% CI: 0.736-0.988, P = .034], IL-2 [OR = 0.836, 95% CI: 0.719-0.972, P = .020], MCP-3 [OR = 0.879, 95% CI: 0.779-0.993, P = .038] had a protective effect on CP. Although mediation analysis identified 13 metabolites mediating the causal relationships between CCL19, CCL23, IFN-gamma, IL-2, IL-6, MCP-3, and CP, none of these mediating effects achieved statistical significance (P > .05). The 2-sample MR analysis in this study provided convincing evidence for the causal effects of circulating inflammatory cytokines on CP, confirming that CCL23, DNER, IL-6, and TNFRSF9 can increase the CP risk, while CCL19, IFN-gamma, IL-10, IL-2, and MCP-3 reduce the CP risk. The evidence was insufficient to prove a direct mediating role of metabolites in the causal relationship between inflammatory cytokines and CP. This study may contribute to a better understanding of the pathogenesis of CP and improve its prevention and treatment.