Early life factors, gene-environment interaction and eosinophilic esophagitis

总结 有了这个建议和未来的研究支持其发现，我们建议测试的假设， 生命早期、产前和产后暴露是嗜酸性粒细胞性食管炎（EoE）的危险因素，特别是在 遗传易感个体核心假设是EoE的风险由复杂的 生命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，早期生活，产前和产后暴露-已知的 破坏肠道微生物群的定殖并被认为改变免疫发育-是EoE的风险因素， 特别是在遗传易感个体中。这项研究建立在我们从早期证据中产生的基础上。 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院、宠物暴露和母乳喂养） 与EoE风险增加相关，某些易感基因型（5 q22 [rs3806932]的TSLP， 15 q13上LOC 283710和KLF 13区域[rs 4329885]，以及CAPN 14 [rs6736278]），与早期生命相互作用 暴露以改变风险。本研究采用基于人群的病例对照研究， 在早期证据的基础上确定EoE案件。具体而言，拟议的研究项目 包括：目标1，一项基于人口的登记研究，对收集的数据进行早期生命因素和EoE的联系研究 前瞻性地，使用基于人群的登记来描述病例和对照，测量主要的 暴露，和潜在的混杂因素;目标2，一项集中的基因-环境相互作用研究， 先前对EoE相关的易感性SNP和早期生命因素的研究;目标3，评估 遗传负荷和遗传负荷与早期生活因素的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以及识别与疾病相关的可能的新基因座 发病机制这些分析不仅将为实现所概述的目标提供证据， 未来，财团为基础的研究基因环境相互作用的EoE。研究小组包括专家 在儿科流行病学（詹森）、遗传流行病学（Langefeld和Martin）、EoE（Dellon）和 免疫学和EoE的遗传学（Rothenberg和Kottyan）。这项研究将汇集一套独特的 国家和国际资源和专门知识。

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.