Early life factors, gene-environment interaction and eosinophilic esophagitis

早期生活因素、基因-环境相互作用与嗜酸粒细胞性食管炎

• 批准号: 10198658
• 负责人: Elizabeth T Jensen
• 金额: $ 37.35万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10198658
• 关键词: 2p23; Address; Admission activity; Adult; Allergens; Allergic Disease; Antibiotics; Autoimmune Diseases; Breast Feeding; Calpain; Candidate Disease Gene; Case-Control Studies; Cesarean section; Chest Pain; Child; Childhood; Chronic; Clinical; Collaborations; Collection; Complex; DNA Sequence; Data; Databases; Deglutition Disorders; Denmark; Development; Digestive System Disorders; Disease; Dizygotic Twins; Environment; Environmental Risk Factor; Eosinophilic Esophagitis; Epidemiology; Esophageal mucous membrane; Etiology; Evaluation; Exposure to; Food; Frequencies; Functional disorder; Future; Gene Expression Regulation; Genetic; Genetic Load; Genetic Predisposition to Disease; Genotype; Growth; Healthcare; Heterogeneity; Immune; Immunology; Impairment; Incidence; Individual; Infiltration; Innate Immune Response; International; Knowledge; Lead; Life; Life Experience; Link; Measures; Mediating; Mediator of activation protein; Methodology; Neonatal Intensive Care; Neonatal Intensive Care Units; Nested Case-Control Study; Newborn Infant; Pathogenesis; Pathway interactions; Pediatric epidemiology; Phenotype; Population Study; Population-Based Registry; Predisposition; Premature Birth; Questionnaires; Registries; Research; Research Project Grants; Research Support; Resources; Risk; Risk Factors; Sampling; Siblings; Susceptibility Gene; TSLP gene; Testing; Vomiting; Work; antenatal; base; biobank; case control; data registry; disorder risk; early life exposure; epidemiology study; experience; gastrointestinal symptom; gene environment interaction; genetic epidemiology; genome wide association study; genomic epidemiology; gut colonization; gut microbiota; immunoregulation; infancy; intrapartum; multidisciplinary; novel; pet animal; population based; postnatal; prospective; protective effect; transcription factor KLF13

SUMMARY With this proposal and the future research supported by its findings, we propose to test the hypothesis that early life, ante- and postnatal exposures are risk factors for eosinophilic esophagitis (EoE), particularly in genetically susceptible individuals. The central hypothesis is that risk of EoE is determined by complex interactions between early-life exposures and susceptibility genes with demonstrated functionality in gene and immune regulation The underlying concept of this work it that early life, ante- and postnatal exposures – known to disrupt colonization of gut microbiota and believed to alter immune development – are risk factors for EoE, particularly in genetically-susceptible individuals. This study builds on early evidence we have generated from single center, case control studies suggesting that certain early life exposures (antibiotic use in infancy, preterm delivery, Cesarean delivery, neonatal intensive care unit admission, pet exposure and breastfeeding) are associated with increased risk of EoE and that certain susceptibility genotypes (TSLP at 5q22 [rs3806932], the LOC283710 and KLF13 region at 15q13 [rs4329885], and CAPN14 [rs6736278]), interact with early life exposures to modify risk. The present study uses a population-based, case-control study with complete case ascertainment of EoE cases to build on this early evidence. Specifically, the proposed research project includes: Aim 1, a population-based registry-linkage study of early life factors and EoE for data collected prospectively, using population-based registries to characterize cases and controls, measure primary exposures, and potential confounders; Aim 2, a focused gene-environment interaction study informed by previous research on susceptibility SNPs and early life factors associated with EoE; and Aim 3, an evaluation of genetic load and genetic load in interaction with early life factors as a means of assessing genotype in context of phenotypic heterogeneity in disease and identifying possible novel loci implicated in disease pathogenesis. These analyses will not only provide evidence to address the aims outlined, but will also inform future, consortium-based studies of gene-environment interaction in EoE. The research team includes experts in pediatric epidemiology (Jensen), genetic epidemiology (Langefeld and Martin), EoE (Dellon), and immunology and the genetics of EoE (Rothenberg and Kottyan). The research will bring together a unique set of national and international resources and expertise.

概括 通过该提案和未来的研究，我们提出了以下假设。 早期生活，产前和产后暴露是嗜酸性静脉炎（EOE）的危险因素，特别是在 遗传易感的个体。中心假设是EOE的风险由复杂确定 早期暴露与敏感性基因之间与基因功能相互作用之间的相互作用 免疫调节这项工作的基本概念是早期生活，产后和产后暴露 - 已知 破坏肠道菌群的定植并被认为会改变免疫发育 - 是EOE的危险因素， 特别是在普通敏感的个体中。这项研究基于我们从 单个中心，案例控制研究表明某些早期生活暴露（婴儿期使用抗生素， 早产，剖宫产，新生儿重症监护病房入场，宠物暴露和母乳喂养） 与EOE的风险增加和某些敏感性基因型有关（TSLP为5q22 [rs3806932]， LOC283710和KLF13区域，位于15Q13 [RS4329885]和CAPN14 [RS6736278]），与早期互动 暴露于改变风险。本研究使用基于人群的病例对照研究，完整案例 确定EOE案件以基于此早期证据。具体而言，拟议的研究项目 包括：AIM 1，一项基于人群的注册表 - 链接研究早期生命因素和收集数据的EOE 前瞻性地，使用基于人群的注册表来表征病例和控制，测量主要 暴露和潜在的混杂因素； AIM 2，一项集中基因环境的相互作用研究。 先前关于与EOE相关的敏感性SNP和早期生命因素的研究；和AIM 3，评估 与早期生命因素相互作用的遗传负荷和遗传负荷作为评估基因型的手段 疾病中表型异质性的背景以及识别与疾病有关的新型基因座 发病。这些分析不仅将提供证据来解决概述的目标，还将告知 未来，基于财团的基因环境相互作用的研究。研究团队包括专家 在小儿流行病学（Jensen），遗传流行病学（Langefeld和Martin），EOE（Delon）和 免疫学和EOE的遗传学（Rothenberg和Kottyan）。该研究将汇集一套独特的集合 国家和国际资源和专业知识。