# Combinatory Effects of Genetic Variants in Eosinophilic Esophagitis

> **NIH NIH K99** · CINCINNATI CHILDRENS HOSP MED CTR · 2021 · $130,362

## Abstract

PROJECT SUMMARY/ABSTRACT
Eosinophilic esophagitis (EoE) is a chronic allergic inflammatory esophageal disorder characterized clinically by
esophageal dysfunction (vomiting, pain, dysphagia, and food impaction); histologically by esophageal
eosinophilia, epithelial hyperplasia, and dilated intercellular spaces associated with impaired barrier function;
and by a high degree of heritability. Most genetic studies have focused on analyzing common genetic variants
by genome-wide association studies (GWAS), with evidence implicating the calpain 14 (CAPN14) and thymic
stromal lymphopoietin (TSLP), which are notably both expressed by the same relevant cell type, esophageal
epithelial cells. Recently, we have performed whole-exome sequencing (WES) on EoE multiplex families and
identified a set of rare genetic variants involved in EoE. Though recent research progress provides the evidence
for EoE genetic etiology being linked to genetic variants, testing single genetic variants separately does not
consider the complex interaction landscape of genes. Our central hypothesis is that a subset of EoE results
from the combination of multiple variants in the same biological pathways. This study will statistically and
experimentally evaluate combinatory effects and how the genetic variants are contributing to EoE and will
develop risk scores based on the biological pathways to predict EoE by using recently developed innovations
(e.g., WES, GWAS, RNA-seq, ChIP-seq, and ex vivo disease modeling [esophageal organoids and organotypic
culture]). In the attached proposal, we have outlined an integrated set of multidisciplinary studies with the
necessary statistical and experimental support to evaluate the impact of the combinatory effects among EoE
genetic variants. In Aim 1, we will test the hypothesis that the risk for EoE will be increased by the combinatory
rare-rare variants, rare-common variants/SNPs, and biological pathways. To determine the impact on the risk
for EoE, we will jointly analyze combinatory effects at variant, gene, and pathway levels. In Aim 2, we will test
the hypothesis that DSP and PPL rare variants have combinatory effects on esophageal barrier functions and
gene/protein expression. To explore the operational mechanisms, we will examine whether these variants have
combinatory effects using ex vivo, 3-dimensional culture models (e.g., esophageal organoids, organotypic
culture) of EoE. Finally, in Aim 3, we will test the hypothesis that the synthesis of genetic and genomic data will
lead to the ability to predict who is at risk of developing EoE, its disease features, and/or response to therapy.
Aim 3 will serve as the foundation for a future R01 application to conduct a mechanistic study to characterize the
impact of convergent genes/pathways and a case-control study to further validate and explore the clinical utility
of risk scores. The proposed study will address an unmet medical need as outlined by a recent NIH workshop,
providing insight int...

## Key facts

- **NIH application ID:** 10189972
- **Project number:** 1K99AI158660-01
- **Recipient organization:** CINCINNATI CHILDRENS HOSP MED CTR
- **Principal Investigator:** Tetsuo Shoda
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $130,362
- **Award type:** 1
- **Project period:** 2021-08-02 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10189972

## Citation

> US National Institutes of Health, RePORTER application 10189972, Combinatory Effects of Genetic Variants in Eosinophilic Esophagitis (1K99AI158660-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10189972. Licensed CC0.

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