@article{a4c17827aaa94a12afb017fd2030b06a,
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.",
author = "Kottyan, {Leah C.} and Davis, {Benjamin P.} and Sherrill, {Joseph D.} and Kan Liu and Mark Rochman and Kenneth Kaufman and Weirauch, {Matthew T.} and Samuel Vaughn and Sara Lazaro and Rupert, {Andrew M.} and Mojtaba Kohram and Stucke, {Emily M.} and Kemme, {Katherine A.} and Albert Magnusen and Hua He and Phillip Dexheimer and Mirna Chehade and Wood, {Robert A.} and Pesek, {Robbie D.} and Vickery, {Brian P.} and Fleischer, {David M.} and Robert Lindbad and Sampson, {Hugh A.} and Mukkada, {Vincent A.} and Putnam, {Phil E.} and Abonia, {J. Pablo} and Martin, {Lisa J.} and Harley, {John B.} and Rothenberg, {Marc E.}",
note = "Funding Information: Funding for this project was provided by the 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) and 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 and P01 AR049084). The CoFAR arm of the study was supported by US NIH grant U19 AI066738 from NIAID and NIDDK. The project was also supported by several grants from the National Center for Research Resources (NCRR), a component of the US NIH: UL1 TR001082 (National Jewish), UL1 TR-000067 (Mount Sinai), UL1 TR-000039 (Arkansas), UL1 TR-000083 (University of North Carolina) and UL1 TR-000424 (Johns Hopkins). Support was also received from the US Department of Veteran Affairs (IMMA 9) and the US Department of Defense (PR094002). This research was supported in part by the Cincinnati Children{\textquoteright}s Research Foundation and its Cincinnati Genomic Control Cohort. Other support was derived from the Campaign Urging Research for Eosinophilic Diseases (CURED), the Buckeye Foundation, the Food Allergy Research Education (FARE) Foundation and the Foundation of the American College of Allergy, Asthma and Immunology. The paper{\textquoteright}s contents are solely the responsibility of the authors and do not necessarily represent the official view of the NCRR or NIH. We also thank S. Hottinger for editorial assistance.",
year = "2014",
month = aug,
doi = "10.1038/ng.3033",
language = "English (US)",
volume = "46",
pages = "895--900",
journal = "Nature genetics",
issn = "1061-4036",
publisher = "Nature Publishing Group",
number = "8",
}