Genome-wide association analysis of eosinophilic esophagitis provides insight into the tissue specificity of this allergic disease
Year: 2021
Type: article
Study design: Observational Study
Abstract: 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.
DOI: 10.17615/vk4g-5457
Authors: Martin, Lisa J., Rochman, Mark, Fleischer, David M., Dexheimer, Phillip, Weirauch, Matthew T., Rupert, Andrew M., Pesek, Robbie D., Lazaro, Sara, Stucke, Emily M., Davis, Benjamin P., Vaughn, Samuel, Kaufman, Kenneth, Sampson, Hugh A., Kemme, Katherine A., Kohram, Mojtaba, Mukkada, Vincent A., Liu, Kan, Chehade, Mirna, Lindbad, Robert, Magnusen, Albert, Vickery, Brian P., Harley, John B., He, Hua, Putnam, Phil E., Sherrill, Joseph D., Wood, Robert A., Kottyan, Leah C., Rothenberg, Marc E., Abonia, J. Pablo
Institution: University of North Carolina at Chapel Hill
Language: English
Topic: Eosinophilic Esophagitis
Subfield: Surgery
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funders: U.S. Department of Defense, Cincinnati Children's Hospital Medical Center, Johns Hopkins University, Buckeye Career Center Foundation, National Institutes of Health, National Heart, Lung, and Blood Institute, National Human Genome Research Institute, National Institute of Allergy and Infectious Diseases, National Institute of Diabetes and Digestive and Kidney Diseases, National Center for Research Resources
Awards: G1068378815, G141320557, G1416531886, Genomics of Lupus, Immunobiology of Food Allergy and Its Treatment, G261638603, G2813733336, G2942865026, G3061070225, G3233018783, G3311179867, UNC Clinical and Translational Science Award, G37449730, G4291336743, G5070799704, G5301882339, Institute for Clinical and Translational Research, G7719837979, G812494088, Mount Sinai Institutes for Clinical and Translational Sciences, G9000001851, G9000006082, G9000016497, G9000020980, G9000048050, G9000050404, G9000052710, G9000147469, G9000169229, G9000169865, G9000298042
OpenAlex ID: W4297980166