Genome-wide association analysis of eosinophilic esophagitis provides insight into the tissue specificity of this allergic disease

• Published in: Nature genetics Vol. 46; no. 8; pp. 895 - 900
• Main Authors: Kottyan, Leah C, Davis, Benjamin P, Sherrill, Joseph D, Liu, Kan, Rochman, Mark, Kaufman, Kenneth, Weirauch, Matthew T, Vaughn, Samuel, Lazaro, Sara, Rupert, Andrew M, Kohram, Mojtaba, Stucke, Emily M, Kemme, Katherine A, Magnusen, Albert, He, Hua, Dexheimer, Phillip, Chehade, Mirna, Wood, Robert A, Pesek, Robbie D, Vickery, Brian P, Fleischer, David M, Lindbad, Robert, Sampson, Hugh A, Mukkada, Vincent A, Putnam, Phil E, Abonia, J Pablo, Martin, Lisa J, Harley, John B, Rothenberg, Marc E
• Format: Journal Article
• Language: English
• Published: United States Nature Publishing Group 01.08.2014
• Subjects: Adolescent; Adult; Allergies; Analysis; B cells; Biopsy; Calpain - genetics; Child; Child, Preschool; Disease; Eosinophilic Esophagitis - genetics; Epigenetic inheritance; Epithelial Cells - metabolism; Esophagitis; Esophagus - metabolism; Female; Food; Food allergies; Gene expression; Genetic aspects; Genetic Predisposition to Disease; Genetic Variation; Genome-Wide Association Study - methods; Genomes; Genotype; Haplotypes; Humans; Interleukin-13 - genetics; Male; Meta-Analysis as Topic; Middle Aged; Models, Genetic; Organ Specificity - genetics; Physiological aspects; Risk factors; Up-Regulation; Young Adult; United States
• ISSN: 1061-4036; 1546-1718; 1546-1718
• DOI: 10.1038/ng.3033

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.