Journal
NATURE GENETICS
Volume 46, Issue 8, Pages 895-900Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ng.3033
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Funding
- US NIH, National Institute of Allergy and Infectious Diseases (NIAID), National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Heart, Lung, and Blood Institute (NHLBI)
- National Human Genome Research Institute (NHGRI) [U19 AI066738, U01 HG006828, U01 HG006828-S1, U01 HG006828-S2, U01 AI066560, R37 AI024717, P01 AI083194, T32 HL7752-19, K23 AI099083, P01 AR049084]
- US NIH from NIAID and NIDDK [U19 AI066738]
- National Center for Research Resources (NCRR), a component of the US NIH [UL1 TR001082, UL1 TR-000067, UL1 TR-000039, UL1 TR-000083, UL1 TR-000424]
- US Department of Veteran Affairs [IMMA 9]
- US Department of Defense [PR094002]
- Cincinnati Children's Research Foundation and its Cincinnati Genomic Control Cohort
- Campaign Urging Research for Eosinophilic Diseases (CURED)
- Buckeye Foundation
- Food Allergy Research Education (FARE) Foundation
- Foundation of the American College of Allergy, Asthma and Immunology
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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 x 10(-16)), we identified an association at 2p23 spanning CAPN14 (P = 2.5 x 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 x 10(-2) < P < 5.1 x 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.
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