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, 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
Nat Genet
Date Published
2014 Aug
Adolescent; Adult; Calpain; Child; Child, Preschool; Eosinophilic Esophagitis; Epithelial Cells; Esophagus; Female; Genetic Predisposition to Disease; Genetic Variation; Genome-Wide Association Study; Genotype; Haplotypes; Humans; Interleukin-13; Male; Meta-Analysis as Topic; Middle Aged; Models, Genetic; Organ Specificity; Up-Regulation; Young Adult

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)