Genome-Wide Association Analysis of Eosinophilic Esophagitis Provides Insight Into the Tissue Specificity of This Allergic Disease

Publication Type
Journal Article
Year of Publication
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
Nat Genet
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Date Published
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.