Genes, Air Pollution, Oxidant Stress, Inflammation and Children's Resp

儿童呼吸系统疾病及其病理生理前兆是重要的临床和公共疾病 既有环境因素又有遗传决定因素的健康问题。尽管已经取得了进展 识别与哮喘发生、呼吸道症状和肺部相关的基因和暴露 功能，需要更多的研究来了解遗传在易感性中的作用，并确定关键的 用于干预的途径和弱势人群。该项目建议调查其贡献 儿童时期炎症反应的遗传变异与1)常见呼吸道疾病的发生 疾病。2)肺功能发育的个体差异，以及3)对不良呼吸的易感性 环境空气污染物的影响。拟议的研究计划建立在丰富的健康、暴露和 儿童健康研究(CHS)的遗传数据来源，这是一项正在进行的队列研究，调查了 南加州11,000多名儿童呼吸系统疾病的遗传和环境因素 孩子们。我们将评估广泛的假设，即相互关联的通路参与炎症 反应(天生的适应系统)和氧化/亚硝化应激1)是儿童期的决定因素 哮喘和肺功能发育，以及2)调节对环境可吸入颗粒物的易感性(PM[0.25]， PM[0.25-2.50]和PM[2.5-10]特性、成分)、臭氧和二氧化氮。我们建议进行一项 途径驱动的候选基因-环境关联研究，以检查 结果(哮喘发病率、呼吸道症状)、肺功能增长和273个关键基因 炎症途径。为了表征每个基因座的遗传贡献，标记SNPs将是 选择的包括保守的SNP或具有编码或调节功能的SNP。社区卫生服务中心的儿童 (n=7700)将对273个基因的6000个SNP进行基因分型，并对每个遗传基因座进行测试 与每种表型的关联。对基因-环境和基因-基因相互作用的子集进行测试将 是基于遗传主效应和基于先验假设的通路拓扑进行的。我们的 采用基于基因型的血统系数的方法，新兴的全球和 具体的关联性测试，以及包括疾病的先前生物学知识的新方法 病理生理学是对全基因组关联研究等发现方法的补充。这个 CHS提供了一个独特的资源来评估关键途径上的基因变异对儿童的影响 呼吸健康。大小、大量的基因数据、高暴露水平和纵向健康数据 使本申请中提出的项目具有可行性、性价比和及时性。这一结果将指导未来 哮喘和慢性阻塞性肺疾病一级和二级预防的机制研究和干预策略 阻塞性呼吸道疾病。

Childhood respiratory diseases and their pathophysiologic antecedents are important clinical and public health problems that have both environmental and genetic determinants. Although progress has been made in identifying the genes and exposures related to asthma occurrence, respiratory symptoms and lung function, more research is needed to understand the role of genetics in susceptibility and identify critical pathways and vulnerable populations for interventions. This project proposes to investigate the contribution of genetic variation in inflammatory responses during childhood to 1) the occurrence of common respiratory diseases. 2) inter-individual differences in lung function growth, and 3) susceptibility for adverse respiratory effects of ambient air pollutants. The proposed program of research builds on the rich health, exposure and genetic data resources of the Children's Health Study (CHS), an ongoing cohort study investigating both genetic and environmental factors related to children's respiratory disease in over 11,000 southern California children. We will assess the broad hypotheses that inter-related pathways involved in inflammatory responses (innate, adaptive systems) and oxidative/nitrosative stress 1) are determinants of childhood asthma and lung function development, and 2) modulate susceptibility to ambient respirable particles (PM[0.25], PM[0.25-2.50, and PM[2.5-10] characteristics, constituents), ozone and nitrogen dioxide. We propose to conduct a pathways-driven candidate gene-environment association study to examine the relationships between outcomes (asthma incidence, respiratory symptoms), lung function growth and 273 key genes in key inflammatory pathways. To characterize the genetic contribution of each locus, tagging SNPs will be selected including conserved SNPs or SNPS with coding or regulatory functions. Children in the CHS (n=7700) would be genotyped for 6,000 SNPs across the 273 genes and each genetic locus tested for associations with each phenotype. Tests of a subset of gene-environment and gene-gene interactions would be conducted based on genetic main effects and a priori hypotheses-based pathway topologies. Our approach that employs genotype-based coefficient of ancestry, emerging analytic methods for global and specific tests of association, and novel methods to include prior biological knowledge of disease pathophysiology is complementary to discovery approaches such as whole genome association studies. The CHS offers a unique resource to assess the effects of genetic variation in critical pathways on children's respiratory health. The size, substantial genotype data, high levels of exposure and longitudinal health data make the project proposed in this application feasible, cost-effective and timely. The results will guide future mechanistic studies and intervention strategies for primary and secondary prevention of asthma and chronic obstructive respiratory diseases.