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 有了这个提议以及其研究结果支持的未来研究，我们建议检验以下假设： 早年、产前和产后接触是嗜酸性粒细胞性食管炎 (EoE) 的危险因素，特别是在 核心假设是 EoE 的风险是由复杂的因素决定的。 早期生命暴露与易感基因之间的相互作用，并已证实基因和 免疫调节 这项工作的基本概念是生命早期、产前和产后的暴露——已知 破坏肠道微生物群的定植并被认为会改变免疫发育——是 EoE 的危险因素， 特别是在遗传易感个体中，这项研究建立在我们获得的早期证据的基础上。 单中心病例对照研究表明，某些早期生命暴露（婴儿期使用抗生素、 早产、剖腹产、新生儿重症监护室入住、宠物接触和母乳喂养） 与 EoE 风险增加相关，并且某些易感基因型（TSLP 位于 5q22 [rs3806932]， 15q13 [rs4329885] 的 LOC283710 和 KLF13 区域以及 CAPN14 [rs6736278]），与早期生命相互作用 本研究采用基于人群的病例对照研究，具有完整的病例。 具体来说，EoE 案例的确定是建立在这一早期证据的基础上的，即拟议的研究项目。 包括： 目标 1，一项基于人群的早期生命因素登记关联研究以及所收集数据的 EoE 前瞻性地，使用基于人群的登记来描述病例和对照的特征，衡量主要 目标 2，一项重点基因-环境相互作用研究，由 先前对与 EoE 相关的易感性 SNP 和早期生命因素的研究以及目标 3 的评估； 遗传负荷和遗传负荷与早期生命因素相互作用作为评估基因型的一种手段 疾病表型异质性的背景并确定与疾病有关的可能的新位点 这些分析不仅将为实现所概述的目标提供证据，而且还将提供信息。 未来基于联盟的 EoE 基因-环境相互作用研究。研究团队包括专家。 儿科流行病学 (Jensen)、遗传流行病学 (Langefeld 和 Martin)、EoE (Dellon) 和 该研究将汇集一组独特的 EoE 免疫学和遗传学（Rothenberg 和 Kottyan）。 国家和国际资源和专业知识。