Combinatory Effects of Genetic Variants in Eosinophilic Esophagitis

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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 into disease genetic mechanisms and thereby potentially contributing to personalized medicine, especially the application of enhanced screening or preventive therapies.