Genome-wide association analysis of eosinophilic esophagitis provides insight into the tissue specificity of this allergic disease
Leah C Kottyan, Benjamin P Davis, Joseph D Sherrill, Kan Liu, Mark Rochman, Kenneth Kaufman, Matthew T Weirauch, Samuel Vaughn, Sara Lazaro, Andrew M Rupert, Mojtaba Kohram, Emily M Stucke, Katherine A Kemme, Albert Magnusen, Hua He, Phillip Dexheimer, Mirna Chehade, Robert A Wood, Robbie D Pesek, Brian P Vickery, David M Fleischer, Robert Lindbad, Hugh A Sampson, Vincent A Mukkada, Phil E Putnam, J Pablo Abonia, Lisa J Martin, John B Harley, Marc E Rothenberg, Leah C Kottyan, Benjamin P Davis, Joseph D Sherrill, Kan Liu, Mark Rochman, Kenneth Kaufman, Matthew T Weirauch, Samuel Vaughn, Sara Lazaro, Andrew M Rupert, Mojtaba Kohram, Emily M Stucke, Katherine A Kemme, Albert Magnusen, Hua He, Phillip Dexheimer, Mirna Chehade, Robert A Wood, Robbie D Pesek, Brian P Vickery, David M Fleischer, Robert Lindbad, Hugh A Sampson, Vincent A Mukkada, Phil E Putnam, J Pablo Abonia, Lisa J Martin, John B Harley, Marc E Rothenberg
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.
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References
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