Gene-Enviroment Interactions and the Origins of Asthma

哮喘是一种常见疾病，具有复杂的病因，包括遗传和 对环境的贡献。儿童哮喘的起源(COSTAR)研究是一项出生队列研究 旨在阐明基因和环境在儿童健康中的相对作用 发育中的免疫系统以及随后的哮喘和过敏风险。在前6年中 这项研究得出了许多重要的发现，为续签申请提供了重点。在……里面 特别是，第一年有症状的鼻病毒(RV)感染是最显著的预测因素 继发性喘息性疾病以及干扰素-γ反应与喘息性疾病的关系 在3岁时，男孩和女孩之间存在差异。最近，我们已经证明了与房车一起喘息 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)和平均干扰素-γ反应在以下年龄段男孩和女孩之间有显著差异 5岁(p=0.0004)。我们进一步确定了基因-环境相互作用与两种轮状病毒疾病 第一年和儿童性别对免疫反应和发育的影响 哮喘和过敏性表型。在此应用程序中，我们建议进一步研究 RV途径中的基因和评估其功能(目标1)，并进一步探索潜在的机制 在9岁(青春期前)和14岁(青春期前后)观察到的干扰素-伽马反应的性别差异 (目标2)。最后，我们建议研究人支气管上皮中的微量(Mi)rna群体。 (BE)细胞感染轮状病毒前后，并检测差异 表达的miRNA基因及其靶点(目标3)。在海岸检测到的所有遗传关联 儿童将在参与图森婴儿免疫研究的儿童身上复制，这是另一项出生 一群人。阐明这些效应的机制可能会提出新的治疗方法或预防措施。 针对高危儿童的策略，并影响我们对这种常见疾病发病机制的理解 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.