Causal relationships between 91 inflammatory cytokines and gastroesophageal reflux disease, and the mediating role of related metabolites: Evidence from genetics

The associations between specific inflammatory cytokines and gastroesophageal reflux disease (GERD) have been confirmed, while their causal relationships remain unclear. We conducted a bidirectional 2-sample Mendelian randomization analysis (MRA) to reveal the causal correlations between 91 inflammatory factors and GERD, thereby conducting a 2-step MRA analysis to reveal the mediating function of 1400 metabolites therein. Data related to 91 inflammatory cytokines were derived from Genome-Wide Association Studies (GWAS) data with 14,824 samples. GWAS data about GERD were obtained from a large genome research project in Finland, including 28,859 GERD cases and 3,50,064 controls. GWAS data about 1400 circulating metabolites were derived from a cohort of 8299 individuals. The inverse variance weighted approach was introduced to obtain the primary MRA results, complemented by 4 additional methods for supportive analyses. Additionally, the study conducted sensitivity analyses with different methods to evaluate heterogeneity and horizontal pleiotropy. Our findings indicated that higher predicted C-X-C motif chemokine 1 [OR = 1.052, 95% CI: 1.004 - 1.103, P = .035], interleukin-1-alpha [OR = 1.083, 95% CI: 1.018 - 1.152, P = .012], and interleukin-4 [IL-4, OR = 1.081, 95% CI: 1.018 - 1.147, P = .011] increased the risk of GERD; whereas tumor necrosis factor ligand superfamily member 12 [OR = 0.958, 95% CI: 0.9174-0.9999, P = .0493] decreased the risk of GERD. No significant statistical differences were found for other inflammatory cytokines. Genetic susceptibility to GERD had no impact on any traits related to circulating inflammatory cytokines. Four metabolites associated with elevated IL-4 levels were identified, including (1-enyl-oleoyl)-GPE (P-18:1), 4-methyl guaiacol sulfate, X-12730, and X-17685, but their mediating effects were not statistically significant (P > .05). This study convincingly proved the causal impact of inflammatory factors on GERD. It confirms that C-X-C motif chemokine 1, interleukin-1-alpha, and IL-4 increase the risk of GERD, while tumor necrosis factor ligand superfamily member 12 reduces it. Additionally, several circulating metabolites are associated with elevated IL-4 levels. However, the evidence for their role as potential mediators in the pathway between IL-4 and GERD risk remains insufficient. The findings of this study propel further comprehension of the pathogenesis of GERD and also point out the therapeutic potential for interventions targeting inflammatory cytokine-targeted inventions.