A Genome-wide Association Study of Childhood Respiratory Outcomes

描述（由申请人提供）： 哮喘是影响儿童的最常见的慢性疾病，是一个主要的临床和公共卫生问题。儿童呼吸系统健康的另一个关键指标是肺功能，最重要的是肺功能发育。儿童时期肺功能发育的缺陷可能导致一生的呼吸系统健康问题，并最终增加成年后的死亡风险。儿童健康研究（CHS）是一项针对11，000多名儿童的持续队列研究，调查空气污染和参与氧化应激和炎症的候选基因对儿童哮喘和肺功能发育的影响。在本提案中，我们将使用来自CHS的大量现有数据来实现以下具体目标： 目标1：使用一组超过300，000个单核苷酸多态性（SNP，优化以标记整个基因组中绝大多数常见的遗传变异）进行全基因组关联研究，以确定增加儿童哮喘风险或影响肺功能发育的新遗传变异。 目标二：通过检测基因-环境相互作用（与臭氧、颗粒物、交通暴露或被动吸烟）和基因-基因相互作用（与GSTM 1），确定与哮喘或肺功能相关的潜在重要途径，以寻找新的遗传变异。 目标3：使用来自CHS的另外两个样本复制我们的基因组筛选中确定的关联，包括父母-后代三人组样本和一组独立的哮喘病例和非哮喘对照。 我们建议使用具有成本效益的多阶段研究设计，该设计将遗传主效应和相互作用的检测统一起来。哮喘和肺功能都是复杂的特征，取决于遗传和环境因素。我们在扫描中使用空气污染和现有候选基因数据的新方法有可能识别出与儿童呼吸健康的重要、既定决定因素协同作用的新基因。 (End摘要）

DESCRIPTION (provided by applicant): Asthma is the most common chronic disease affecting children and is a major clinical and public health problem. Another key indicator of children's respiratory health is lung function, and most importantly, lung function development. Deficits in lung function development as a child can lead to a lifetime of respiratory health problems and ultimately, to increased risk of mortality later in adult life. The Children's Health Study (CHS) is an ongoing cohort study of over 11,000 children, investigating the impact of air pollution and candidate genes involved in oxidative stress and inflammation on both childhood asthma and lung function development. In this proposal, we will use the extensive existing data from the CHS to accomplish the following specific aims: Aim 1: To conduct a genome-wide association study using a panel of over 300,000 single nucleotide polymorphisms (SNPs, optimized to tag the vast majority of common genetic variation in the entire genome) to identify new genetic variants that increase risk of childhood asthma or affect lung function development. Aim 2: To identify potentially important pathways related to asthma or lung function, by testing for gene-environment interaction (with ozone, particulate matter, traffic exposure, or passive tobacco smoke), and gene-gene interaction (with GSTM1) in the search for new genetic variants. Aim 3: To replicate associations identified in our genome screen using two additional samples derived from the CHS, including a sample of parent-offspring trios and a large independent set of asthmatic cases and non-asthmatic controls. We propose to use a cost-efficient multi-stage study design that unifies the detection of genetic main effects and interactions. Both asthma and lung function are complex traits that depend on both genetic and environmental factors. Our novel use of air-pollution and existing candidate-gene data in the scan has the potential to identify new genes that act synergistically with important, established determinants of children's respiratory health. (End of Abstract)