# Mechanisms of genetic risk at 2p23 in Eosinophilic Esophagitis

> **NIH NIH R01** · CINCINNATI CHILDRENS HOSP MED CTR · 2020 · $351,000

## Abstract

Abstract
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.

## Key facts

- **NIH application ID:** 9990753
- **Project number:** 5R01DK107502-05
- **Recipient organization:** CINCINNATI CHILDRENS HOSP MED CTR
- **Principal Investigator:** Leah Claire Kottyan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $351,000
- **Award type:** 5
- **Project period:** 2016-09-01 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9990753

## Citation

> US National Institutes of Health, RePORTER application 9990753, Mechanisms of genetic risk at 2p23 in Eosinophilic Esophagitis (5R01DK107502-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9990753. Licensed CC0.

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