Replication and meta-analyses nominate numerous eosinophilic esophagitis risk genes

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY

卷:147

Article

Kottyan, Leah C.^1,2,3  Trimarchi, Michael P.¹  Lu, Xiaoming²  Caldwell, Julie M.¹  Maddox, Avery²  Parameswaran, Sreeja²  Lape, Michael^2,4  D'Mello, Rahul J.^1,5  Bonfield, Madeline⁵  Ballaban, Adina¹  Mukkada, Vincent^3,6  Putnam, Philip E.^3,6  Abonia, Pablo^1,2  Morgenstern, Netali Ben-Baruch¹  Eapen, Amy A.^1,2  Wen, Ting^1,3  Weirauch, Matthew T.^2,3,7,8  Rothenberg, Marc E.^1,3 

[1] Cincinnati Childrens Hosp Med Ctr, Div Allergy & Immunol, Cincinnati, OH 45229 USA

[2] Cincinnati Childrens Hosp Med Ctr, Ctr Autoimmune Genom & Etiol, Cincinnati, OH 45229 USA

[3] Univ Cincinnati, Coll Med, Dept Pediat, Cincinnati, OH USA

[4] Univ Cincinnati, Coll Med, Grad Program Biomed Informat, Cincinnati, OH USA

[5] Univ Cincinnati, Coll Med, Immunol Grad Program, Cincinnati, OH USA

[6] Cincinnati Childrens Hosp Med Ctr, Div Gastroenterol Hepatol & Nutr, Cincinnati, OH 45229 USA

[7] Cincinnati Childrens Hosp Med Ctr, Div Biomed Informat, Cincinnati, OH 45229 USA

[8] Cincinnati Childrens Hosp Med Ctr, Div Dev Biol, Cincinnati, OH 45229 USA

关键词: Allergy;    genetics;    esophagitis;    eosinophil;    epithelium;    polymorphism;    variant;    atopy;   

DOI  :  10.1016/j.jaci.2020.10.018

来源: Elsevier

【 摘 要 】

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.

【 授权许可】

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