Mechanisms of genetic risk at 2p23 in Eosinophilic Esophagitis

嗜酸性粒细胞性食管炎 2p23 的遗传风险机制

• 批准号: 9552809
• 负责人: Leah Claire Kottyan
• 金额: $ 35.1万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9552809
• 关键词: 11q13; 2p23; Address; Adult; Alleles; Allergic; Allergic Disease; Allergic rhinitis; Asthma; Atopic Dermatitis; Automobile Driving; Binding; Biochemical; Biological; Calcium; Calpain; Childhood; Chronic; Chronic Disease; Clinical; Data; Data Set; Development; Diagnosis; Disease; Educational workshop; Eosinophilia; Eosinophilic Esophagitis; Epithelial; Epithelial Cells; Equation; Esophageal; Esophagus; Etiology; Excision; Family; Feedback; Food; Gastrointestinal Diseases; Gene Deletion; Gene Silencing; Genes; Genetic; Genetic Epistasis; Genetic Risk; Genotype; Goals; Haplotypes; Hypersensitivity; Immunologics; Impairment; In Vitro; Individual; Inflammation; Inflammation Mediators; Inflammatory; Interleukin-13; Lead; Link; Mediating; Mediator of activation protein; Medical; Modeling; Modification; Molecular; Morphology; Mucous Membrane; Pathogenesis; Pathway interactions; Patients; Peptide Hydrolases; Phenotype; Predisposition; Proteins; Publishing; Recording of previous events; Recurrence; Regulation; Risk; Role; Signal Transduction; Susceptibility Gene; TSLP gene; Testing; Time; Tissues; Transcript; United States National Institutes of Health; Untranslated RNA; Variant; allergic response; atopy; base; clinical predictors; cohort; design; eosinophil; experimental study; functional genomics; genetic linkage; genetic risk factor; genetic variant; genome wide association study; genome-wide; improved; innovation; member; overexpression; public health relevance; repaired; response; risk variant; statistics; transcription factor

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.

抽象的 嗜酸性食管炎（EOE）是一种以食道为标志的慢性过敏性胃肠道疾病 嗜酸性粒细胞从小到成年一直持续存在。 EOE领域和过敏的中心问题之一 通常，要了解为什么个人会发展出某些过敏性疾病的表现，例如EOE。 我们最近发现，除了过敏敏化遗传危险因素外，EOE敏感性与 在2P23处的遗传基因座，编码CAPN14基因和Calpain-14蛋白。这个遗传联系已经 在多个队列中复制以及最近的独立研究，增添了信誉 2P23遗传联系。 Calpain-14以前尚未在我们最近的新数据集之外进行研究。然而， 其他经典Calpains其他成员的已知底物包括与 过敏反应。我们将CAPN14确定为EOE疾病活动的函数动态上调 和遗传单倍型，以及上皮细胞暴露于IL-13之后。在初步研究中，我们有 确定了一组内含子和基因内遗传变异，这些变异最有可能是因果而增加的EOE 风险。我们还生成了数据，证实了Calpain-14在疾病诱导和 维修。使用这些结果，我们提出了一组目标，旨在测试我们的中心假设 EOE的开发是由遗传危险因素介导的，其中包括广义特应性的相互作用 易感基因座（11Q13/5Q22）和涉及CAPN14的EOE食管反应。我们将测试这个 通过关注解释基因型依赖性调节的功能机制来假设 CAPN14表达（AIM 1）以及Calpain-14的下游目标和调节作用（AIM 2）。基于 根据我们的假设，即Calpain-14在IL-13介导的炎症的背景下起作用，我们将评估 通过诊断统计，在2P23处遗传变异的临床预测效用增加了 伴有过敏性鼻炎，哮喘或特应性皮炎和其他关键的遗传基因座（AIM 3）。这些 实验是及时的，因为它们解决了最近的NIH研讨会概述的未满足的医疗需求（请参阅 Bochner等人Jaci； PMCID：PMC3432981和PA-15-027）。通过一组三个目标测试 互补的假设，我们提供了剖析重要疾病并实现真实疾病的机会 朝着全球了解功能基因组，生化，炎症和互动的进展 通过2P23和CALPAIN-14增加EOE风险的机制。