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: 10441396
• 负责人: Elizabeth T Jensen
• 金额: $ 24.22万
• 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/10441396
• 关键词: 2p23; Address; Admission activity; Adult; Algorithms; Allergens; Allergic Disease; Antibiotics; Autoimmune Diseases; Blood; 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; Early identification; Environment; Environmental Risk Factor; Eosinophilic Esophagitis; Eosinophilic Infiltrate; 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; Innate Immune Response; International; Knowledge; Life; Life Experience; Link; Measures; Mediating; Mediator; Methodology; Neonatal Intensive Care; Neonatal Intensive Care Units; 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; Spottings; Susceptibility Gene; TSLP gene; Testing; Vomiting; Work; adaptive immune response; antenatal; 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.

摘要 有了这一提议和由其发现支持的未来研究，我们建议检验以下假设 早期生活、产前和产后暴露是嗜酸性食管炎(EoE)的危险因素，尤其是在 遗传易感的个体。中心假设是EoE的风险由复杂性决定 早期暴露与易感基因之间的相互作用 免疫调节这项工作的基本概念是，早期生命、产前和出生后的暴露-已知 扰乱肠道微生物区系的定植并被认为改变免疫发育-是EoE的风险因素， 尤其是在遗传易感的个体中。这项研究建立在我们从 单中心病例对照研究表明，某些早期生命暴露(婴儿时期使用抗生素， 早产、剖腹产、新生儿重症监护病房入院、宠物暴露和母乳喂养) 与EoE风险增加和某些易感基因类型(5q22处的TSLP[rs3806932]， 位于15q13的LOC283710和KLF13区域[rs4329885]和CAPN14[rs6736278]与早期生命相互作用 风险敞口以修正风险。本研究采用以人群为基础的病例对照研究。 确定EoE病例以此为基础的早期证据。具体地说，拟议的研究项目 包括：Aim 1，收集的数据的早期生命因素和EoE的基于人群的登记-联系研究 前瞻性地，使用基于人口的登记来确定病例和对照的特征，测量初级 暴露和潜在的混杂因素；Aim 2，一项专注于基因-环境相互作用的研究，由 与EoE相关的易感性SNPs和早期生活因素的先前研究；以及Aim 3，一项评估 遗传负荷和遗传负荷与早期生命因素的相互作用作为一种评估基因突变的方法 疾病表型异质性的背景和识别可能与疾病有关的新基因座 发病机制。这些分析不仅将为解决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中基因-环境相互作用的研究。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 免疫学和EoE遗传学(Rothenberg和Kottyan)。这项研究将带来一套独特的 国家和国际资源和专门知识。

项目成果

Maternal and Infant Antibiotic and Acid Suppressant Use and Risk of Eosinophilic Esophagitis.

母婴抗生素和抑酸剂的使用和嗜酸性粒细胞性食管炎的风险。

• DOI: 10.1001/jamapediatrics.2023.4609
• 发表时间: 2023
• 期刊: JAMA pediatrics
• 影响因子: 26.1
• 作者: Jensen,ElizabethT;Svane,HeleneM;Erichsen,Rune;Kurt,Gencer;Heide-Jorgensen,Uffe;Sorensen,HenrikT;Dellon,EvanS
• 通讯作者: Dellon,EvanS

Prenatal, Intrapartum, and Neonatal Factors Increase the Risk of Eosinophilic Esophagitis.

产前、产时和新生儿因素会增加嗜酸性粒细胞性食管炎的风险。

• DOI: 10.14309/ajg.0000000000002303
• 发表时间: 2023
• 期刊: The American journal of gastroenterology
• 作者: Kurt,Gencer;Svane,HeleneML;Erichsen,Rune;Heide-Jørgensen,Uffe;Sørensen,HenrikT;Dellon,EvanS;Jensen,ElizabethT
• 通讯作者: Jensen,ElizabethT