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.

儿童期呼吸道疾病及其病理生理学的前因是重要的临床和公众 具有环境和遗传决定因素的健康问题。虽然取得了进展 在识别与哮喘发生有关的基因和暴露时，呼吸道症状和肺 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 干预措施的途径和脆弱人群。该项目建议调查贡献 儿童期炎症反应的遗传变异至1）常见呼吸的发生 疾病。 2）个体间肺功能生长的差异，3）不良呼吸的敏感性 环境空气污染物的影响。拟议的研究计划建立在富裕的健康，暴露和 儿童健康研究（CHS）的遗传数据资源，一项正在进行的人群研究，研究两者 与11,000多个南加州儿童呼吸道疾病有关的遗传和环境因素 孩子们。我们将评估涉及炎症相关途径的广泛假设 反应（先天，自适应系统）和氧化/亚硝化压力1）是儿童期的决定因素 哮喘和肺功能发育，以及2）调节对环境可呼吸颗粒的敏感性（PM [0.25]， PM [0.25-2.50和PM [2.5-10]特征，成分），臭氧和二氧化氮。我们建议进行 途径驱动的候选基因环境协会研究 结局（哮喘发病率，呼吸道症状），肺功能生长和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SNP将是 选定的包括具有编码或调节功能的保守SNP或SNP。 CHS中的孩子 （n = 7700）将在273个基因上为6,000个SNP进行基因分型，每个遗传基因座测试 与每个表型的关联。基因环境和基因 - 基因相互作用的一部分的测试将 根据遗传主要影响和先验假设的途径拓扑进行进行。我们的 采用基于基因型的祖先系数，全球和新兴分析方法的方法 缔合的特定测试和包括先前疾病生物学知识的新方法 病理生理学是对整个基因组关联研究等发现方法的补充。这 CHS提供了一种独特的资源来评估关键途径中遗传变异的影响 呼吸健康。大小，大量基因型数据，高水平的暴露和纵向健康数据 使该项目在此应用程序中提出可行，具有成本效益和及时的可行性。结果将指导未来 机械研究和干预策略，用于预防哮喘和慢性的初级和次要预防 阻塞性呼吸道疾病。