期刊
JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY
卷 147, 期 1, 页码 255-266出版社
MOSBY-ELSEVIER
DOI: 10.1016/j.jaci.2020.10.018
关键词
Allergy; genetics; esophagitis; eosinophil; epithelium; polymorphism; variant; atopy
资金
- Consortium of Food Allergy Researchers (COFAR, National Institute of Allergy and Infectious Diseases grant) [U19AI066738]
The study identified 6 replicated association and genome-wide significance loci, as well as 7 additional loci with suggestive significance. Thirteen protein-coding EoE candidate risk genes were expressed in a genotype-dependent manner.
Background: Eosinophilic esophagitis (EoE) is an emerging, chronic, rare allergic disease associated with marked eosinophil accumulation in the esophagus. Previous genome-wide association studies have provided strong evidence for 3 genomewide susceptibility loci. Objective: We sought to replicate known and suggestive EoE genetic risk loci and conduct a meta-analysis of previously reported data sets. Methods: An EoE-Custom single-nucleotide polymophism (SNP) Chip containing 956 candidate EoE risk single-nucleotide polymorphisms was used to genotype 627 cases and 365 controls. Statistical power was enhanced by adding 1959 external controls and performing meta-analyses with 2 independent EoE genome-wide association studies. Results: Meta-analysis identified replicated association and genome-wide significance at 6 loci: 2p23 (2 independent genetic effects) and 5q22, 10p14, 11q13, and 16p13. Seven additional loci were identified at suggestive significance (P < 10(-6)): 1q31, 5q23, 6q15, 6q21, 8p21, 17q12, and 22q13. From these risk loci, 13 protein-coding EoE candidate risk genes were expressed in a genotype-dependent manner. EoE risk genes were expressed in disease-relevant cell types, including esophageal epithelia, fibroblasts, and immune cells, with some expressed as a function of disease activity. The genetic risk burden of EoE-associated genetic variants was markedly larger in cases relative to controls (P < 10(-38)); individuals with the highest decile of genetic burden had greater than 12-fold risk of EoE compared with those within the lowest decile. Conclusions: This study extends the genetic underpinnings of EoE, highlighting 13 genes whose genotype-dependent expression expands our etiologic understanding of EoE and provides a framework for a polygenic risk score to be validated in future studies.
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