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Nat Genet. 2014 Aug;46(8):895-900. doi: 10.1038/ng.3033. Epub 2014 Jul 13.

Genome-wide association analysis of eosinophilic esophagitis provides insight into the tissue specificity of this allergic disease.

Author information

1
1] Center for Autoimmune Genomics and Etiology, Department of Pediatrics, Division of Rheumatology, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio, USA. [2] US Department of Veterans Affairs Medical Center, Cincinnati, Ohio, USA. [3] Department of Pediatrics, Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio, USA. [4].
2
1] Department of Pediatrics, Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio, USA. [2].
3
Department of Pediatrics, Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio, USA.
4
1] Center for Autoimmune Genomics and Etiology, Department of Pediatrics, Division of Rheumatology, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio, USA. [2] US Department of Veterans Affairs Medical Center, Cincinnati, Ohio, USA.
5
1] Center for Autoimmune Genomics and Etiology, Department of Pediatrics, Division of Rheumatology, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio, USA. [2] Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio, USA.
6
Center for Autoimmune Genomics and Etiology, Department of Pediatrics, Division of Rheumatology, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio, USA.
7
Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio, USA.
8
Department of Pediatrics, Division of Human Genetics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio, USA.
9
Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
10
Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
11
Department of Pediatrics, University of Arkansas for Medical Sciences and Arkansas Children's Hospital, Little Rock, Arkansas, USA.
12
Department of Pediatrics, University of North Carolina, Chapel Hill, North Carolina, USA.
13
Department of Pediatrics, National Jewish Health, Denver, Colorado, USA.
14
The EMMES Corporation, Rockville, Maryland, USA.
15
Department of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio, USA.
16
1] Center for Autoimmune Genomics and Etiology, Department of Pediatrics, Division of Rheumatology, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio, USA. [2] US Department of Veterans Affairs Medical Center, Cincinnati, Ohio, USA. [3].

Abstract

Eosinophilic esophagitis (EoE) is a chronic inflammatory disorder associated with allergic hypersensitivity to food. We interrogated >1.5 million genetic variants in EoE cases of European ancestry and subsequently in a multi-site cohort with local and out-of-study control subjects. In addition to replicating association of the 5q22 locus (meta-analysis P=1.9×10(-16)), we identified an association at 2p23 spanning CAPN14 (P=2.5×10(-10)). CAPN14 was specifically expressed in the esophagus, was dynamically upregulated as a function of disease activity and genetic haplotype and after exposure of epithelial cells to interleukin (IL)-13, and was located in an epigenetic hotspot modified by IL-13. Genes neighboring the top 208 EoE-associated sequence variants were enriched for esophageal expression, and multiple loci for allergic sensitization were associated with EoE susceptibility (4.8×10(-2)<P<5.1×10(-11)). We propose a model to explain the tissue-specific nature of EoE that involves the interplay of allergic sensitization with an EoE-specific, IL-13-inducible esophageal response involving CAPN14.

PMID:
25017104
PMCID:
PMC4121957
DOI:
10.1038/ng.3033
[Indexed for MEDLINE]
Free PMC Article

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