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

描述(申请人提供)：哮喘是一种多因素疾病，与环境和遗传因素有关。我们证明，早年接触空气污染和烟草造成的危害在不同的种族/民族之间是不同的。我们最近的全基因组关联研究已经确定了共同的和种族特有的哮喘遗传风险因素和哮喘相关特征。我们的发现表明，基因和早期环境暴露都是少数族裔儿童哮喘易感性的重要因素。我们假设，哮喘易感性的种族/民族差异是由于早年接触空气污染和烟草导致的基因-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-混合作图和新的全基因组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世系与环境交互作用分析。我们将使用对当地染色体祖先(非洲人、欧洲人和美洲原住民)的全基因组估计来对来自美国各地的6,536名拉丁裔和非裔美国儿童进行按环境(AXE)扫描的混合图谱(AXE)扫描。我们将通过对CAAPA和千基因组计划的基因分型和归因于SNP的有针对性的GxE分析来精细绘制AXE相互作用峰。结果将在墨西哥城儿童哮喘研究(MCCAS)中使用类似的结果和暴露。具体目标2：患有和不患有哮喘的不同种族儿童哮喘的全基因组环境(GxE)交互作用分析。我们将使用一种新的两步分析方法对3890万个SNPs进行全基因组扫描，以确定GxE与空气污染和烟草烟雾暴露的相互作用。扫描将在我们8,138名儿童的联合资源中进行，以及在拉丁裔、欧洲人和非洲裔美国人小组中进行。结果将在MCCAS中使用类似的结果和暴露情况进行复制。预期结果：我们将确定基因和遗传位点，基因-环境相互作用在哮喘病因学中发挥重要作用，从而找回哮喘缺失的部分遗传性。我们将确定重要的共享和种族 具体的基因-环境相互作用，这将进一步加深我们对哮喘易感性的种族/民族差异的理解。

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.