Estimation of Peptic Ulcer Risk Through Mendelian Randomization Analyses Using Genetically Predicted Circulating Levels of Cytokines

Abstract

Background: The relationship between inflammatory cytokines and peptic ulcer disease (PUD) has been reported in several observational studies, but causal inference remains uncertain. This study aimed to investigate the causal association between 41 circulating cytokines and PUD using Mendelian randomization (MR) analysis.

Methods: We performed a two-sample MR analysis using genetic variation data from a large genome-wide association study (GWAS) of peptic ulcer (130 European cases and 189,695 controls) and cytokine-related GWAS data from 8,293 healthy individuals. The inverse variance weighted (IVW) method was used as the primary analysis, supported by sensitivity analyses including MR-Egger, weighted median, simple model, weighted model, and MR-PRESSO.

Results: Our findings suggest that platelet-derived growth factor-BB (PDGF-BB), stromal cell-derived factor-1α (SDF-1A), and macrophage inflammatory protein-1α (MIP-1A) are associated with PUD risk. Specifically, genetically predicted PDGF-BB was positively associated with ulcer risk (ORIVW = 4.15; 95% CI: 1.74–9.87; P = 0.0013), while higher levels of MIP-1A (ORIVW = 0.20; 95% CI: 0.07–0.59; P = 0.0037) and SDF-1A (ORIVW = 0.32; 95% CI: 0.12–0.87; P = 0.0249) were protective.

Conclusion: This MR study indicates that PDGF-BB may increase susceptibility to PUD, whereas MIP-1A and SDF-1A appear protective. These findings strengthen the evidence for cytokines as potential biomarkers and therapeutic targets in PUD.