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

基因、空气污染、氧化应激、炎症和儿童呼吸

• 批准号: 8279266
• 负责人: FRANK D. GILLILAND
• 金额: $ 44.01万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-06-01 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8279266
• 关键词: Adult; Affect; Air Pollutants; Air Pollution; Asthma; Biological; California; Candidate Disease Gene; Characteristics; Child; Child health care; Childhood; Childhood Asthma; Chronic Obstructive Asthma; Clinical; Code; Cohort Studies; Critical Pathways; Data; Development; Disease; Environment; Environmental Risk Factor; Exposure to; Functional disorder; Future; Genes; Genetic; Genetic Determinism; Genetic Variation; Genotype; Growth; Health; Incidence; Individual Differences; Inflammation; Inflammatory; Inflammatory Response; Intervention; Knowledge; Lung diseases; Methods; Nitrogen Dioxide; Outcome; Ozone; Particulate Matter; Pathway interactions; Phenotype; Population Intervention; Predisposition; Primary Prevention; Public Health; Research; Resources; Respiratory physiology; Role; Schools; Secondary Prevention; Symptoms; System; Testing; Tobacco smoke; Vulnerable Populations; base; cost effective; follow-up; gene interaction; genetic variant; genome wide association study; nitrosative stress; novel; oxidant stress; particle; programs; respiratory; trafficking; young adult

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.

儿童呼吸系统疾病及其病理生理学背景对于临床和公众都很重要 具有环境和遗传决定因素的健康问题。虽然已经取得了进展 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学在易感性中的作用并确定关键的 干预措施的途径和弱势群体。本项目拟调查贡献 儿童时期炎症反应的遗传变异导致 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) 对不良呼吸系统的易感性 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，调查了这两种情况 与南加州 11,000 多名儿童呼吸道疾病相关的遗传和环境因素 孩子们。我们将评估涉及炎症的相互关联途径的广泛假设 反应（先天、适应性系统）和氧化/亚硝化应激 1) 是童年的决定因素 哮喘和肺功能发育，2) 调节对环境可吸入颗粒物 (PM[0.25]、 PM[0.25-2.50、PM[2.5-10]特征、成分）、臭氧和二氧化氮。我们建议开展一次 路径驱动的候选基因-环境关联研究，以检查之间的关系 结果（哮喘发病率、呼吸道症状）、肺功能生长和关键基因中的 273 个关键基因 炎症途径。为了表征每个位点的遗传贡献，将标记 SNP 选择的包括保守的SNP或具有编码或调节功能的SNPS。 CHS 儿童 (n=7700) 将针对 273 个基因的 6,000 个 SNP 进行基因分型，并对每个基因位点进行测试 与每个表型的关联。对基因-环境和基因-基因相互作用的子集的测试将 基于遗传主效应和基于先验假设的通路拓扑进行。我们的 采用基于基因型的祖先系数的方法，新兴的全球和 特定的关联测试以及包含疾病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 CHS 提供了独特的资源来评估关键途径遗传变异对儿童的影响 呼吸系统健康。规模、大量基因型数据、高水平暴露和纵向健康数据 使本申请中提出的项目可行、具有成本效益且及时。结果将指导未来 哮喘和慢性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。