Journal article
Genome-wide association analysis of eosinophilic esophagitis provides insight into the tissue specificity of this allergic disease
Nature genetics, Vol.46(8), pp.895-900
08/2014
DOI: 10.1038/ng.3033
PMCID: PMC4121957
PMID: 25017104
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.
Details
- Title: Subtitle
- Genome-wide association analysis of eosinophilic esophagitis provides insight into the tissue specificity of this allergic disease
- Creators
- Leah C Kottyan - 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. US Department of Veterans Affairs Medical Center, Cincinnati, Ohio, USA. Department of Pediatrics, Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio, USA.Benjamin P Davis - 1] Department of Pediatrics, Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio, USA.Joseph D Sherrill - Department of Pediatrics, Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio, USAKan Liu - Department of Pediatrics, Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio, USAMark Rochman - Department of Pediatrics, Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio, USAKenneth Kaufman - 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. US Department of Veterans Affairs Medical Center, Cincinnati, Ohio, USAMatthew T Weirauch - 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. Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio, USASamuel Vaughn - Center for Autoimmune Genomics and Etiology, Department of Pediatrics, Division of Rheumatology, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio, USASara Lazaro - 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. US Department of Veterans Affairs Medical Center, Cincinnati, Ohio, USAAndrew M Rupert - Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio, USAMojtaba Kohram - Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio, USAEmily M Stucke - Department of Pediatrics, Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio, USAKatherine A Kemme - Department of Pediatrics, Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio, USAAlbert Magnusen - 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. US Department of Veterans Affairs Medical Center, Cincinnati, Ohio, USAHua He - Department of Pediatrics, Division of Human Genetics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio, USAPhillip Dexheimer - Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio, USAMirna Chehade - Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, New York, USARobert A Wood - Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland, USARobbie D Pesek - Department of Pediatrics, University of Arkansas for Medical Sciences and Arkansas Children's Hospital, Little Rock, Arkansas, USABrian P Vickery - Department of Pediatrics, University of North Carolina, Chapel Hill, North Carolina, USADavid M Fleischer - Department of Pediatrics, National Jewish Health, Denver, Colorado, USARobert Lindbad - The EMMES Corporation, Rockville, Maryland, USAHugh A Sampson - Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, New York, USAVincent A Mukkada - Department of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio, USAPhil E Putnam - Department of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio, USAJ Pablo Abonia - Department of Pediatrics, Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio, USALisa J Martin - Department of Pediatrics, Division of Human Genetics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio, USAJohn B Harley - 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. US Department of Veterans Affairs Medical Center, Cincinnati, Ohio, USA.Marc E Rothenberg - 1] Department of Pediatrics, Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio, USA.
- Resource Type
- Journal article
- Publication Details
- Nature genetics, Vol.46(8), pp.895-900
- DOI
- 10.1038/ng.3033
- PMID
- 25017104
- PMCID
- PMC4121957
- NLM abbreviation
- Nat Genet
- ISSN
- 1061-4036
- eISSN
- 1546-1718
- Publisher
- Springer Science and Business Media LLC
- Grant note
- P30 DK078392 / NIDDK NIH HHS UL1 RR029887 / NCRR NIH HHS T32 AI060515 / NIAID NIH HHS T32 GM063483 / NIGMS NIH HHS U01 HG006828-S2 / NHGRI NIH HHS U19 AI066738 / NIAID NIH HHS I01 BX001834 / BLRD VA T32 HL7752-19 / NHLBI NIH HHS UL1 TR001425 / NCATS NIH HHS P30 AR047363 / NIAMS NIH HHS U01 HG006828-S1 / NHGRI NIH HHS UL1 TR-000083 / NCATS NIH HHS UL1 TR001082 / NCATS NIH HHS UL1 TR-000067 / NCATS NIH HHS UL1 TR-000039 / NCATS NIH HHS UL1 TR-000424 / NCATS NIH HHS
- Language
- English
- Date published
- 08/2014
- Academic Unit
- Stead Family Department of Pediatrics; Immunology; Internal Medicine
- Record Identifier
- 9984093327702771
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