Eosinophilic Esophagitis (EoE) is a chronic, allergic gastrointestinal disorder marked by esophageal eosinophilia persisting from childhood into adulthood. One of the central questions in the EoE field, and allergy in general, is to understand why individuals develop certain manifestations of allergic disease, such as EoE. We have recently found that in addition to allergic sensitization genetic risk factors, EoE susceptibility is linked to a genetic locus at 2p23, encoding the CAPN14 gene and calpain-14 protein. This genetic linkage has been replicated in multiple cohorts, as well as a recent independent study, adding credence to the importance of the 2p23 genetic linkage. Calpain-14 has not been previously studied outside of our recent new dataset; however, known substrates for other members of the classical calpains include inflammatory mediators relevant for allergic responses. We identified CAPN14 as dynamically up-regulated as a function of EoE disease activity and genetic haplotype, as well as after exposure of epithelial cells to IL-13. In preliminary studies, we have identified a set of intronic and intragenic genetic variants that are most likely to be causal for increased EoE risk. We have also generated data substantiating a regulatory role for calpain-14 in both disease induction and repair. Using these results, we propose a set of aims designed to test our central hypothesis that the development of EoE is mediated by genetic risk factors that include the interplay of generalized atopy susceptibility loci (11q13/5q22) and an EoE esophageal response involving CAPN14. We will test this hypothesis by focusing on functional mechanisms that account for the genotype-dependent regulation of CAPN14 expression (Aim 1) and the downstream targets and regulatory role of calpain-14 (Aim 2). Based upon our hypothesis that calpain-14 functions in the context of IL-13-mediated inflammation, we will assess the increased clinical predictive utility of genetic variants at 2p23 through the statistical consideration of diagnosis with allergic rhinitis, asthma, or atopic dermatitis and other key atopy associated genetic loci (Aim 3). These experiments are timely, as they address an unmet medical need as outlined by a recent NIH workshop (see Bochner et al JACI; PMCID: PMC3432981 and PA-15-027). Through a set of three aims testing complementary hypotheses, we present an opportunity to dissect an important disease and make real progress towards a global understanding of the functional genomic, biochemical, inflammatory, and interactive mechanisms that increase risk of EoE through 2p23 and calpain-14.

Public Health Relevance

) Eosinophilic esophagitis (EoE) is a chronic disease that is strongly linked to calpain-14 (encoded by CAPN14); however, we do not know what controls the expression of CAPN14 or what calpain-14 is doing biologically. Herein, we elucidate the functional genomic mechanisms driving CAPN14 expression and increased risk of EoE at the 2p23 locus. The proposal will uncover fundamental mechanisms of EoE pathogenesis with broad scientific and clinical implications.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
Project #
Application #
Study Section
Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section (HAI)
Program Officer
Perrin, Peter J
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Cincinnati Children's Hospital Medical Center
United States
Zip Code
Harley, John B; Chen, Xiaoting; Pujato, Mario et al. (2018) Transcription factors operate across disease loci, with EBNA2 implicated in autoimmunity. Nat Genet 50:699-707
Martin, Lisa J; He, Hua; Collins, Margaret H et al. (2018) Eosinophilic esophagitis (EoE) genetic susceptibility is mediated by synergistic interactions between EoE-specific and general atopic disease loci. J Allergy Clin Immunol 141:1690-1698
Patel, Zubin; Lu, Xiaoming; Miller, Daniel et al. (2018) A plausibly causal functional lupus-associated risk variant in the STAT1-STAT4 locus. Hum Mol Genet :
Sherrill, Joseph D; Kc, Kiran; Wang, Xinjian et al. (2018) Whole-exome sequencing uncovers oxidoreductases DHTKD1 and OGDHL as linkers between mitochondrial dysfunction and eosinophilic esophagitis. JCI Insight 3:
Spergel, Jonathan M; Aceves, Seema S; Kliewer, Kara et al. (2018) New developments in patients with eosinophilic gastrointestinal diseases presented at the CEGIR/TIGERS Symposium at the 2018 American Academy of Allergy, Asthma & Immunology Meeting. J Allergy Clin Immunol 142:48-53
Azouz, Nurit P; Ynga-Durand, Mario A; Caldwell, Julie M et al. (2018) The antiprotease SPINK7 serves as an inhibitory checkpoint for esophageal epithelial inflammatory responses. Sci Transl Med 10:
Kottyan, Leah C; Maddox, Avery; Braxton, Julian R et al. (2018) Genetic variants at the 16p13 locus confer risk for eosinophilic esophagitis. Genes Immun :
Kottyan, L C; Rothenberg, M E (2017) Genetics of eosinophilic esophagitis. Mucosal Immunol 10:580-588
Litosh, Vladislav A; Rochman, Mark; Rymer, Jeffrey K et al. (2017) Calpain-14 and its association with eosinophilic esophagitis. J Allergy Clin Immunol 139:1762-1771.e7
Langefeld, Carl D; Ainsworth, Hannah C; Cunninghame Graham, Deborah S et al. (2017) Transancestral mapping and genetic load in systemic lupus erythematosus. Nat Commun 8:16021

Showing the most recent 10 out of 13 publications