Genome-Wide Association Analysis of Eosinophilic Esophagitis Provides Insight Into the Tissue Specificity of This Allergic Disease
08/2014
Journal Article
Authors:
Kottyan, L.;
Davis, B.;
Sherrill, J.;
Liu, K.;
Rochman, M.;
Kaufman, K.;
Weirauch, M.;
Vaughn, S.;
Lazaro, S.;
Rupert, A.;
Kohram, M.;
Stucke, E.;
Kemme, K.;
, ;
Lindblad, R.;
Sampson, H.;
Mukkada, V.;
Putnam, P.;
Abonia, J.;
Martin, L.;
Harley, J.;
Rothenberg, M.
Secondary:
Nat Genet
Volume:
46
Pagination:
895-900
URL:
http://www.ncbi.nlm.nih.gov/pubmed/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.
