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.

项目摘要/摘要 嗜酸性食管炎（EOE）是一种慢性过敏性食管疾病，其特征是 食管功能障碍（呕吐，疼痛，吞咽困难和食物撞击）；组织学通过食管 嗜酸性粒细胞，上皮增生和与屏障功能受损相关的细胞间空间； 并具有很高的遗传力。大多数遗传研究都集中于分析常见遗传变异 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 基质淋巴细胞增生素（TSLP），这两个均由相同的相关细胞类型表达 上皮细胞。最近，我们在EOE多重族和 确定了EOE中涉及的一组稀有遗传变异。尽管最近的研究进度提供了证据 对于EOE遗传病因与遗传变异相关，测试单个遗传变异不分别 考虑基因的复杂相互作用景观。我们的中心假设是EOE的子集 从同一生物途径中多个变体的组合。这项研究将从统计和 实验评估组合效应以及遗传变异如何对EOE贡献并将 通过使用最近开发的创新来根据生物学途径来建立风险评分来预测EOE （例如，WES，GWAS，RNA-SEQ，CHIP-SEQ和EX VIVO疾病模型[食管器官和器官型 文化]）。在附带的提案中，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，以评估EOE组合效应的影响 遗传变异。在AIM 1中，我们将检验以下假设：组合将增加EOE的风险 稀有的稀有变体，稀有式变体/SNP和生物途径。确定对风险的影响 对于EOE，我们将共同分析变体，基因和途径水平的组合效应。在AIM 2中，我们将测试 DSP和PPL稀有变体对食管屏障功能和 基因/蛋白质表达。为了探索操作机制，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，器官，器官型）的组合效应 EOE的文化。最后，在AIM 3中，我们将检验以下假设：遗传和基因组数据的合成 导致能够预测谁有发展EOE的风险，其疾病特征和/或对治疗的反应。 AIM 3将作为未来R01应用的基础，以进行机械研究以表征 收敛基因/途径和病例对照研究的影响，以进一步验证和探索临床实用性 风险分数。拟议的研究将解决未满足的医疗需求，如最近的NIH研讨会所述 提供有关疾病遗传机制的见解，从而有可能导致个性化医学， 特别是应用增强筛查或预防疗法的应用。