Gene-Enviroment Interactions and the Origins of Asthma

哮喘是一种常见的疾病，其病因复杂，包括遗传和 环境贡献。哮喘儿童起源（COAST）研究是一项出生队列研究 旨在阐明基因和环境对高风险儿童的相对作用， 发展免疫系统和随后的哮喘和过敏的风险。在最初的6年里， 这项研究发现了许多重要的发现，这些发现提供了这项更新申请的重点。在 特别是，第一年有症状的鼻病毒（RV）感染是最重要的预测因子， 随后的喘息性疾病，以及IFN-γ反应和喘息之间的关系 在3岁时，男孩和女孩之间存在差异。最近，我们发现RV喘息 第一年的感染是5岁时喘息（p = 0.00047）和5岁时哮喘的重要预测因素。 6岁（p = 0.000095）和平均IFN-γ反应在男孩和女孩之间存在显著差异， 年龄5岁（p = 0.0004）。我们进一步确定了基因-环境相互作用与RV疾病， 第一年和儿童的性别影响免疫反应和发展， 哮喘和过敏表型。在本申请中，我们建议进一步研究 基因在RV途径和评估其功能（目的1），并进一步探索潜在的机制 9岁（青春期前）和14岁（青春期前期）时观察到的IFN-γ反应的性别差异 (Aim 2）。最后，我们建议研究人支气管上皮细胞中的微（mi）RNA群体， (BE)在RV感染前后的细胞中，并检查差异表达中的多态性。 表达的miRNA基因及其靶点（Aim 3）。在COAST中检测到的所有遗传关联 儿童将在参加图森婴儿免疫研究的儿童中复制， 队列。阐明这些作用的机制可能会提出新的治疗或预防方法 策略，并影响我们对这种常见的发病机制的理解。 疾病

Asthma is a common disease with a complex etiology that includes both genetic and environmental contributions. The Childhood Origins of ASThma (COAST) study is a birth cohort study of high risk children designed to elucidate the relative roles of genes and environment on the developing immune system and subsequent risk for asthma and allergy. During the first 6 years of this study many important findings emerged that provide the focus of this renewal application. In particular, symptomatic rhinovirus (RV) infection in the first year was the most significant predictor of subsequent wheezing illnesses, and the relationship between IFN-gamma responses and wheezing at age 3 differed between boys and girls. More recently we have shown that wheezing with RV infection in the first year is a significant predictor of wheezing at age 5 (p = 0.00047) and asthma at age 6 (p = 0.000095) and mean IFN-gamma responses differ significantly between boys and girls at age 5 (p = 0.0004). We have further identified gene-environment interactions with both RV illness in the first year and with child's sex that influence immune responsiveness and the development of asthma and allergic phenotypes. In this application, we propose to further investigate the role of genes in RV pathways and asses their function (Aim 1) and to further explore potential mechanisms for the observed sex differences in IFN-gamma responses at age 9 (pre-puberty) and age 14 (peripuberty) (Aim 2). Lastly, we propose to study micro(mi)RNA populations in human bronchial epithelial (BE) cells before and after infection with RV, and to examine polymorphisms in the differentially expressed miRNA genes and their targets (Aim 3). All genetic associations detected in the COAST children will be replicated in children participating in the Tucson Infant Immune Study, another birth cohort. Elucidating the mechanisms for these effects could suggest novel therapies or prevention strategies for at-risk children and impact our understanding of the pathogenesis of this common disease.