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

儿童呼吸道疾病及其病理生理学前因是重要的临床和公共卫生问题。 这些健康问题既有环境因素，也有遗传因素。虽然已经取得了进展 在确定与哮喘发生、呼吸道症状和肺部疾病相关的基因和暴露方面， 功能，需要更多的研究来了解遗传学在易感性中的作用，并确定关键的 路径和弱势群体进行干预。本项目旨在研究 儿童期炎症反应的遗传变异与1）常见呼吸道疾病的发生有关， 疾病2)肺功能发育的个体间差异，以及3）对不良呼吸道感染的易感性 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）的遗传数据资源，这是一项正在进行的队列研究， 在南加州的11,000多名儿童中， 孩子我们将评估广泛的假设，即参与炎症反应的相互关联的途径， 反应（先天的，适应性系统）和氧化/亚硝化应激1）是童年的决定因素 哮喘和肺功能发展，和2）调节对周围可吸入颗粒物（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 路径驱动的候选基因-环境关联研究，以检查 结果（哮喘发病率，呼吸道症状），肺功能生长和273个关键基因， 炎症通路。为了表征每个基因座的遗传贡献，将标记SNP。 选择包括保守的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个基因中的6,000个SNP进行基因分型，每个基因座检测 与每一个表型的关联。对基因-环境和基因-基因相互作用子集的测试将 基于遗传主效应和基于先验假设的通路拓扑结构进行。我们 采用基于基因型的祖先系数的方法，全球和 关联的特定测试，以及包括疾病的先前生物学知识的新方法 病理生理学是对诸如全基因组关联研究的发现方法的补充。的 CHS提供了一个独特的资源，以评估关键途径中遗传变异对儿童发育的影响。 呼吸道健康规模，大量的基因型数据，高水平的暴露和纵向健康数据 使本申请中提出的项目切实可行、具有成本效益和及时。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.