title: Genome-wide association analysis of eosinophilic esophagitis provides insight into the tissue specificity of this allergic disease.
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.
authors.affiliation: 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].
authors.forename: Leah C
authors.initials: LC
authors.lastname: Kottyan
authors.affiliation: 1] Department of Pediatrics, Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio, USA. [2].
authors.forename: Benjamin P
authors.initials: BP
authors.lastname: Davis
authors.affiliation: Department of Pediatrics, Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio, USA.
authors.forename: Joseph D
authors.initials: JD
authors.lastname: Sherrill
authors.affiliation: Department of Pediatrics, Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio, USA.
authors.forename: Kan
authors.initials: K
authors.lastname: Liu
authors.affiliation: Department of Pediatrics, Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Rochman
authors.affiliation: 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.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Kaufman
authors.affiliation: 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.
authors.forename: Matthew T
authors.initials: MT
authors.lastname: Weirauch
authors.affiliation: Center for Autoimmune Genomics and Etiology, Department of Pediatrics, Division of Rheumatology, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio, USA.
authors.forename: Samuel
authors.initials: S
authors.lastname: Vaughn
authors.affiliation: 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.
authors.forename: Sara
authors.initials: S
authors.lastname: Lazaro
authors.affiliation: Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio, USA.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Rupert
authors.affiliation: Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio, USA.
authors.forename: Mojtaba
authors.initials: M
authors.lastname: Kohram
authors.affiliation: Department of Pediatrics, Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio, USA.
authors.forename: Emily M
authors.initials: EM
authors.lastname: Stucke
authors.affiliation: Department of Pediatrics, Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio, USA.
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Kemme
authors.affiliation: 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.
authors.forename: Albert
authors.initials: A
authors.lastname: Magnusen
authors.affiliation: Department of Pediatrics, Division of Human Genetics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio, USA.
authors.forename: Hua
authors.initials: H
authors.lastname: He
authors.affiliation: Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio, USA.
authors.forename: Phillip
authors.initials: P
authors.lastname: Dexheimer
authors.affiliation: Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Mirna
authors.initials: M
authors.lastname: Chehade
authors.affiliation: Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Wood
authors.affiliation: Department of Pediatrics, University of Arkansas for Medical Sciences and Arkansas Children's Hospital, Little Rock, Arkansas, USA.
authors.forename: Robbie D
authors.initials: RD
authors.lastname: Pesek
authors.affiliation: Department of Pediatrics, University of North Carolina, Chapel Hill, North Carolina, USA.
authors.forename: Brian P
authors.initials: BP
authors.lastname: Vickery
authors.affiliation: Department of Pediatrics, National Jewish Health, Denver, Colorado, USA.
authors.forename: David M
authors.initials: DM
authors.lastname: Fleischer
authors.affiliation: The EMMES Corporation, Rockville, Maryland, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Lindbad
authors.affiliation: Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Hugh A
authors.initials: HA
authors.lastname: Sampson
authors.affiliation: Department of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio, USA.
authors.forename: Vincent A
authors.initials: VA
authors.lastname: Mukkada
authors.affiliation: Department of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio, USA.
authors.forename: Phil E
authors.initials: PE
authors.lastname: Putnam
authors.affiliation: Department of Pediatrics, Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio, USA.
authors.forename: J Pablo
authors.initials: JP
authors.lastname: Abonia
authors.affiliation: Department of Pediatrics, Division of Human Genetics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio, USA.
authors.forename: Lisa J
authors.initials: LJ
authors.lastname: Martin
authors.affiliation: 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].
authors.forename: John B
authors.initials: JB
authors.lastname: Harley
authors.affiliation: 1] Department of Pediatrics, Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio, USA. [2].
authors.forename: Marc E
authors.initials: ME
authors.lastname: Rothenberg
mesh_terms: D000293:Adolescent; D000328:Adult; D002154:Calpain / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D057765:Eosinophilic Esophagitis / Q000235:genetics*; D004847:Epithelial Cells / Q000378:metabolism; D004947:Esophagus / Q000378:metabolism; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D055106:Genome-Wide Association Study / Q000379:methods; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D018793:Interleukin-13 / Q000235:genetics; D008297:Male; D015201:Meta-Analysis as Topic; D008875:Middle Aged; D008957:Models, Genetic; D009928:Organ Specificity / Q000235:genetics; D015854:Up-Regulation; D055815:Young Adult
chemical_list: D018793:Interleukin-13; D002154:Calpain; C527669:CAPNS1 protein, human