Gene-Environment Analyses of Early Life Exposures and Asthma in Ethnically Diverse Children

不同种族儿童早期生命暴露和哮喘的基因环境分析

基本信息

批准号：
8806186
负责人：
Esteban Gonzalez Burchard
金额：
$ 17.6万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-12-01 至 2017-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8806186
关键词：
Admixture African African American Air Pollution Asthma Child Childhood Asthma Chronic Disease Cities Disease Environment Environmental Exposure Ethnic group Etiology European Exposure to Genes Genetic Genome Genome Scan Genotype Goals Heritability Knowledge Latino Life Maps Measures Meta-Analysis Methods Mexican Mexico Minority Native Americans Nitrogen Dioxide Outcome Participant Phase Phenotype Play Pollution Population Population Heterogeneity Predisposition Prevalence Prevention Reporting Resources Risk Role Scanning Single Nucleotide Polymorphism Smoking Socioeconomic Status Subgroup Techniques Testing Tobacco Tobacco smoke Work analytical method early life exposure environmental change gene environment interaction genetic association genetic risk factor genome wide association study genome-wide health disparity in utero novel public health relevance racial and ethnic racial/ethnic difference tobacco exposure trait

项目摘要

DESCRIPTION (provided by applicant): Asthma is a multifactorial disease with environmental and genetic contributions. We demonstrated that the harm caused by early-life exposures to air pollution and tobacco varies among different racial/ethnic groups. Our recent genome-wide association studies have identified both shared and ethnic-specific genetic risk factors for asthma and asthma-related traits. Our findings imply that both genes and early-life environmental exposures are important contributors to asthma susceptibility in minority children. We hypothesize that racial/ethnic differences in asthma susceptibility are due to gene-environment interactions resulting from early-life exposure to air pollution and tobacco. We will use existing genome-wide SNP genotypes and two distinct but complimentary approaches-admixture mapping and novel genome-wide GxE interaction scanning methods-to investigate the relationship between genetics, early-life air pollution and tobacco smoke exposures, and asthma risk. Specific Aim 1: Ancestry by environment interaction analysis of asthma in minority children. We will use genome-wide estimates of local chromosomal ancestry (African, European, and Native American) to perform an admixture mapping by environment (AxE) scan in 6,536 Latino and African American children from across the U.S. We will fine map AxE interaction peaks by performing targeted GxE analyses of genotyped and imputed SNPs from CAAPA and the Thousand Genomes Project. Results will be replicated using similar outcomes and exposures in the Mexico City Childhood Asthma Study (MCCAS). Specific Aim 2: Genome-wide by environment (GxE) interaction analysis of asthma in ethnically diverse children with and without asthma. We will use a novel two-step analytical method to perform a genome-wide scan at 38.9 million SNPs for GxE interactions with air pollution and tobacco smoke exposure. Scans will be performed in our combined resource of 8,138 children, as well as within Latino, European, and African American subgroups. Results will be replicated using similar outcomes and exposures in MCCAS. EXPECTED OUTCOMES: We will identify genes and genetic loci whereby gene-environment interactions play an important role in asthma etiology, and thus retrieve part of the missing heritability of asthma. We will identify significant shared and ethnic specific gene-environment interactions, which will further our understanding of racial/ethnic differences in asthma susceptibility.

描述（由申请人提供）：哮喘是一种多因素疾病，受环境和遗传影响。我们证明，早年接触空气污染和烟草所造成的危害因种族/族裔群体而异。我们最近的全基因组关联研究已经确定了哮喘和哮喘相关特征的共同遗传风险因素和种族特异性遗传风险因素。我们的研究结果表明，基因和早期环境暴露都是少数民族儿童哮喘易感性的重要影响因素。我们假设哮喘易感性的种族/民族差异是由于生命早期接触空气污染和烟草而导致的基因与环境相互作用造成的。我们将使用现有的全基因组 SNP 基因型和两种不同但互补的方法（混合作图和新型全基因组 GxE 相互作用扫描方法）来研究遗传学、早期空气污染和烟草烟雾暴露以及哮喘风险之间的关系。具体目标 1：少数民族儿童哮喘的环境相互作用分析的祖先。我们将使用对当地染色体血统（非洲、欧洲和美洲原住民）的全基因组估计，对来自美国各地的 6,536 名拉丁裔和非裔美国儿童进行环境混合映射 (AxE) 扫描。我们将通过以下方式精细映射轴交互峰值：对 CAAPA 和千人基因组计划的基因分型和推算 SNP 进行针对性 GxE 分析。将使用墨西哥城儿童哮喘研究 (MCCAS) 中类似的结果和暴露来复制结果。具体目标 2：对患有和不患有哮喘的不同种族儿童进行哮喘的全基因组环境 (GxE) 相互作用分析。我们将使用一种新颖的两步分析方法对 3890 万个 SNP 进行全基因组扫描，以了解 GxE 与空气污染和烟草烟雾暴露之间的相互作用。扫描将在我们的 8,138 名儿童以及拉丁裔、欧洲人和非裔美国人子群体中进行。将使用 MCCAS 中的类似结果和暴露来复制结果。预期结果：我们将确定基因和基因位点，使基因与环境的相互作用在哮喘病因学中发挥重要作用，从而恢复部分缺失的哮喘遗传性。我们将确定重要的共同和种族特定的基因-环境相互作用，这将进一步我们对哮喘易感性的种族/民族差异的理解。