Professionals

Authors
Trimarchi MP et al.

Journal
Journal of Allergy and Clinical Immunology 2026
PubMed ID: 41865802

Paper of the Month – Selected and discussed by Francesca Racca

🎯 Study Aim

The authors sought  to identify novel genetic risk loci for eosinophilic esophagitis (EoE) by leveraging shared genetic architecture with other atopic diseases and to develop a polygenic risk score (PRS) for EoE.

🔬 Methods

A genome-wide association study (GWAS) was conducted comprising 1,757 cases with EoE and 14,467 population controls. Multi-trait analysis of GWAS (MTAG) was subsequently applied, integrating EoE data with GWAS summary statistics from other atopic diseases (UK Biobank; >450,000 subjects). Functional analyses were performed to nominate candidate EoE risk genes. PRS models derived from MTAG were compared with PRS derived from the EoE-specific GWAS. An interactive web tool (EGIDExpress) was developed to facilitate dataset queries and visualization.

📊 Key Findings

• The EoE-specific GWAS identified 11 independent risk variants across 8 loci, including 3 novel loci.
• MTAG identified 33 independent EoE risk variants across 24 loci, including 14 novel loci.
• Functional studies nominated 90 candidate EoE risk genes, implicating mechanisms beyond type 2 immunity.
• MTAG-derived PRS outperformed PRS derived from the EoE-specific GWAS.

Additional findings

• One new male-specific locus was discovered.

🧠 Interpretation

These findings expand the EoE genetic risk loci landscape and highlight the substantial polygenic contribution to EoE susceptibility. Moreover, they confirm extensive shared mechanisms between EoE and topic diseases. In particular, these findings confirm calpain 14 as an EoE- specific susceptibility factor and the role of multiple  genes implicated in the pathogenetic pathways shared between EoE and atopic diseases, including  TSLP, TGFbeta, TNFalpha, IL-4, IL-13 and STAT6 signaling. This study also implicates genes involved in T cell selection, protease inhibition, epidermal differentiation, DNA damage response, and homing signals broadening the pathophysiology of EoE beyond the Type-2 inflammation, eosinophils and Th2 cells to encompass innate immunity, fibroblasts, epithelial cells, macrophages, ILC2 and Th17.

The validated PRS enables future genetic risk assessment.

⚠️ Critical Appraisal

• Limited reliability of atopic diseases diagnoses:
  • Self-reported diagnosis of allergic rhinitis and atopic dermatitis were accepted for diagnosis in EoE cohorts
  • Atopy diagnosis in UK Biobank relied on ICD codes
• IgE-mediated food allergy, the atopic comorbidity most strongly associated with EoE, was excluded due to lack of robust GWAS data
• Analysis restricted to patients of European ancestry.

📝 Take-Home Message

Genetic studies continue to expand our understanding of EoE pathophysiology as a polygenic disease that shares many pathways with other atopic diseases while retaining specific risk factors. The identification of genetic loci involved in functions beyond the classic type 2-inflammation may reveal novel therapeutic targets. Future studies incorporating higher diagnostic accuracy for atopic diseases and diverse ethnicity populations are warranted.