Combinatory Effects of Genetic Variants in Eosinophilic Esophagitis

嗜酸性粒细胞性食管炎中遗传变异的联合作用

• 批准号: 10460607
• 负责人: Tetsuo Shoda
• 金额: $ 13.03万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-02 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10460607
• 关键词: 3-Dimensional; Address; Allergic; Allergic Disease; Autoimmune; Bioinformatics; Biological; Biological Models; Biology; CRISPR/Cas technology; Calpain; Case-Control Studies; ChIP-seq; Chronic; Clinical; Collaborations; Complex; Data; Deglutition Disorders; Desmosomes; Disease; Disease model; Disease susceptibility; Educational workshop; Eosinophilia; Eosinophilic Esophagitis; Epithelial; Epithelial Cells; Esophageal Diseases; Esophagus; Etiology; Extracellular Space; Family; Food; Foundations; Functional disorder; Future; Gene Deletion; Gene Frequency; Gene Proteins; Genes; Genetic; Genetic Predisposition to Disease; Genetic Variation; Genetic study; Genome; Genomics; Heritability; Histologic; Human Genetics; Hyperplasia; Impairment; Inflammatory; Knowledge; Link; Medical; Medicine; Modeling; Monozygotic twins; Multiomic Data; Odds Ratio; Organoids; Pain; Pathway interactions; Patients; Phenotype; Positioning Attribute; Preventive therapy; Process; Research; Research Design; Resources; Risk; Siblings; Single Nucleotide Polymorphism; TSLP gene; Testing; Twin Studies; United States National Institutes of Health; Variant; Vomiting; Weight; Widespread Disease; analytical method; base; biobank; cell type; cohort; exome sequencing; gene interaction; genetic variant; genome wide association study; genomic data; innovation; insight; multidisciplinary; next generation sequencing; novel; personalized medicine; protein expression; rare condition; rare variant; risk variant; screening; skills; stem cells; transcriptome sequencing; treatment response

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.

项目概要/摘要 嗜酸性粒细胞性食管炎（EoE）是一种慢性过敏性炎症性食管疾病，其临床特征为 食道功能障碍（呕吐、疼痛、吞咽困难和食物嵌塞）；组织学上通过食管 与屏障功能受损相关的嗜酸性粒细胞增多、上皮增生和细胞间隙扩张； 并具有高度的遗传力。大多数遗传学研究都集中于分析常见的遗传变异 通过全基因组关联研究 (GWAS)，有证据表明钙蛋白酶 14 (CAPN14) 和胸腺 基质淋巴细胞生成素 (TSLP)，值得注意的是，它们均由相同的相关细胞类型（食管细胞）表达 上皮细胞。最近，我们对 EoE 多重家族进行了全外显子组测序 (WES) 鉴定了一组与 EoE 相关的罕见遗传变异。尽管最近的研究进展提供了证据 对于与遗传变异相关的 EoE 遗传病因，单独测试单个遗传变异并不 考虑基因复杂的相互作用景观。我们的中心假设是 EoE 结果的一个子集 来自相同生物途径中多种变体的组合。本研究将通过统计和 通过实验评估组合效应以及遗传变异如何促进 EoE 并将 使用最近开发的创新技术，根据生物途径制定风险评分，以预测 EoE （例如，WES、GWAS、RNA-seq、ChIP-seq 和离体疾病模型 [食管类器官和器官型 文化]）。在所附提案中，我们概述了一套综合的多学科研究 必要的统计和实验支持来评估 EoE 之间组合效应的影响 遗传变异。在目标 1 中，我们将检验以下假设：EoE 风险会因组合措施而增加 罕见-罕见变异、罕见-常见变异/SNP 以及生物途径。确定对风险的影响 对于EoE，我们将共同分析变异、基因和通路水平的组合效应。在目标 2 中，我们将测试 DSP 和 PPL 罕见变异对食管屏障功能具有组合效应的假设 基因/蛋白质表达。为了探索其运作机制，我们将检查这些变体是否具有 使用离体、3维培养模型（例如食管类器官、器官型 文化）的EoE。最后，在目标 3 中，我们将检验以下假设：遗传和基因组数据的综合将 能够预测谁有患 EoE 的风险、其疾病特征和/或对治疗的反应。 目标 3 将作为未来 R01 应用的基础，以进行机制研究来表征 趋同基因/通路的影响和病例对照研究，以进一步验证和探索临床效用 风险评分。拟议的研究将解决最近 NIH 研讨会概述的未满足的医疗需求， 提供对疾病遗传机制的洞察，从而可能有助于个性化医疗， 特别是加强筛查或预防性治疗的应用。