The role of circulating cytokines in eosinophilic esophagitis: A Mendelian randomization and gene expression analysis study.

This study aimed to explore potential causal relationships between 91 circulating inflammatory cytokines and eosinophilic esophagitis (EoE) using a two-sample Mendelian randomization (MR) framework, with findings further examined at the transcriptomic level. We conducted a two-sample MR analysis utilizing summary-level genome-wide association studies data. The inverse-variance weighted method was used for the primary analysis, supplemented by sensitivity analyses (MR-Egger, weighted median) to assess pleiotropy. A false discovery rate (FDR) was applied to correct for multiple comparisons. Subsequently, we performed a differential expression analysis of the GSE197702 dataset, containing esophageal biopsies from a pediatric cohort with a significance threshold of adjusted P-value < .05. Our MR analysis identified nominally significant associations where genetically predicted higher levels of interleukin-8 (IL-8) and C-C motif chemokine ligand 19 (CCL19) were associated with an increased risk of EoE, whereas higher levels of hepatocyte growth factor were associated with a decreased risk (P < .05; P_fdr < .2). Sensitivity analyses showed no evidence of significant horizontal pleiotropy. Complementing the genetic finding for IL-8, our transcriptomic analysis observed that the gene encoding IL-8, chemokine ligand 8 (CXCL8), was upregulated in esophageal tissues from EoE patients compared to healthy controls. Integrating genetic and transcriptomic insights, this study suggests a potential link between the IL-8 pathway and EoE pathogenesis. Given that the MR associations were suggestive after FDR correction, these findings should be considered exploratory. Nevertheless, they highlight the IL-8 pathway as a candidate target warranting further mechanistic and clinical validation.