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

Eosinophilic esophagitis (EoE) is a chronic inflammatory disorder associated with allergic hypersensitivity to food. We interrogated >1.5 million genetic variants in European EoE cases and subsequently in a multi-site cohort with local and out-of-study control subjects. In addition to replication...

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Detalles Bibliográficos
Autores principales: 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, Vince, Putnam, Phil E., Abonia, J. Pablo, Martin, Lisa J., Harley, John B., Rothenberg, Marc E.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4121957/
https://www.ncbi.nlm.nih.gov/pubmed/25017104
http://dx.doi.org/10.1038/ng.3033
Descripción
Sumario:Eosinophilic esophagitis (EoE) is a chronic inflammatory disorder associated with allergic hypersensitivity to food. We interrogated >1.5 million genetic variants in European EoE cases and subsequently in a multi-site cohort with local and out-of-study control subjects. In addition to replication of the 5q22 locus (meta-analysis p = 1.9×10(−16)), we identified association at 2p23 (encoding CAPN14, p = 2.5×10(−10)). CAPN14 was specifically expressed in the esophagus, dynamically upregulated as a function of disease activity and genetic haplotype and after exposure of epithelial cells to IL-13, and located in an epigenetic hotspot modified by IL-13. There was enriched esophageal expression for the genes neighboring the top 208 EoE sequence variants. Multiple allergic sensitization loci were associated with EoE susceptibility (4.8×10(−2) < p < 5.1×10(−11)). We propose a model that elucidates the tissue specific nature of EoE that involves the interplay of allergic sensitization with an EoE-specific, IL-13–inducible esophageal response involving CAPN14.