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Author Spotlight: Investigating the Pathophysiology of Eosinophilic Esophagitis
Published on: May 10, 2024
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Replication and meta-analyses nominate numerous eosinophilic esophagitis risk genes
Leah C Kottyan1, Michael P Trimarchi2, Xiaoming Lu3
1Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Center for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Department of Pediatrics, University of Cincinnati, College of Medicine, Cincinnati, Ohio.
The Journal of Allergy and Clinical Immunology
|January 15, 2021
Summary
This study identifies 13 new genes linked to eosinophilic esophagitis (EoE) risk. Genotype-dependent gene expression in disease-relevant cells deepens our understanding of this rare allergic condition.
Area of Science:
- Genetics
- Immunology
- Gastroenterology
Background:
- Eosinophilic esophagitis (EoE) is a chronic, rare allergic disease characterized by eosinophil buildup in the esophagus.
- Previous genome-wide association studies (GWAS) have identified three primary genetic susceptibility loci for EoE.
Purpose of the Study:
- To replicate known and suggestive genetic risk loci for EoE.
- To conduct a comprehensive meta-analysis of existing EoE genetic datasets.
- To identify novel genetic risk factors contributing to EoE etiology.
Main Methods:
- Genotyping of 627 cases and 365 controls using an EoE-Custom single-nucleotide polymorphism (SNP) Chip.
- Inclusion of 1959 external controls to enhance statistical power.
- Meta-analysis of current data with two independent EoE GWAS datasets.
Main Results:
- Meta-analysis confirmed genome-wide significance at six loci (2p23, 5q22, 10p14, 11q13, 16p13), with two independent effects at 2p23.
- Seven additional loci reached suggestive significance (P < 10^-6), including 1q31, 5q23, 6q15, 6q21, 8p21, 17q12, and 22q13.
- Thirteen protein-coding genes within these risk loci showed genotype-dependent expression in disease-relevant cells, and a higher genetic risk burden was strongly associated with increased EoE risk (OR > 12).
Conclusions:
- This study expands the genetic landscape of EoE by identifying 13 candidate risk genes.
- The genotype-dependent expression of these genes provides new insights into the etiology of EoE.
- The findings lay the groundwork for developing a polygenic risk score for EoE.
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