Familial Eosinophilic Esophagitis: A Systems-Level Analysis of Immune and Epithelial Transcriptional Programs

Abstract

Eosinophilic esophagitis (EoE) is a chronic, immune-mediated disorder marked by esophageal
eosinophilic infiltration and a Th2-skewed inflammatory profile. Familial aggregation, with a
sevenfold increased risk among first-degree relatives, suggests a strong genetic component,
though the molecular mechanisms linking inherited risk to disease onset remain unclear.

To investigate this, we analyzed RNA sequencing data (GSE250595) from esophageal biopsies
of 68 individuals: 43 EoE patients, 6 unaffected relatives, and 19 unrelated healthy controls.
Differential expression analysis (DESeq2), Gene Ontology (GO) enrichment, and Weighted
Gene Co-expression Network Analysis (WGCNA) were applied to uncover pathways and gene
modules associated with disease status.

Our results revealed immune activation and extracellular matrix remodeling as dominant features
in affected individuals, whereas unaffected relatives showed enrichment for antigen presentation
and immune surveillance pathways. WGCNA identified three key modules: (1) the MEblue
module—positively correlated with healthy controls—was enriched for epithelial maintenance
and stress-response genes (e.g., HSPA5, HIF1A); (2) the MEgreen module, linked to disease,
included immune signaling genes (CD4, FN1) and three EoE-associated rare variants (MUC16,
ADGRE1, TENM3); and (3) the MEturquoise module, enriched for proliferative and survival
pathways involving TP53 and AKT1. Notably, zinc ion response genes—including MT1X,
MT1E, and MT2A—were downregulated in patients and clustered within the MEblue module,
indicating impaired epithelial stress adaptation and barrier repair.

These findings suggest that familial EoE involves loss of protective transcriptional programs
alongside activation of inflammatory and proliferative signaling. Our integrative analysis
highlights zinc dysregulation and immune overactivation as central to disease progression,
offering mechanistic insight and potential avenues for early intervention in genetically
predisposed individuals.