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

描述（由申请人提供）：哮喘是一种多因素疾病，具有环境和遗传贡献。我们证明了早期暴露于空气污染和烟草所造成的危害在不同种族/民族之间存在差异。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，基因和早期生活环境暴露是少数民族儿童哮喘易感性的重要贡献者。我们假设哮喘易感性的种族/民族差异是由于早期暴露于空气污染和烟草导致的基因-环境相互作用。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与哮喘风险之间的关系。具体目标1：分析少数民族儿童哮喘与环境的相互作用。我们将使用当地染色体祖先（非洲人，欧洲人和美洲原住民）的全基因组估计值，对来自美国各地的6，536名拉丁裔和非洲裔美国儿童进行环境混合映射（AxE）扫描。我们将通过对CAAPA和千人基因组计划的基因分型和插补SNP进行有针对性的GxE分析，精细映射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进行复制。具体目标2：在不同种族的哮喘和非哮喘儿童中进行全基因组环境（GxE）相互作用分析。我们将使用一种新型的两步分析方法对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的相互作用。扫描将在我们的8，138名儿童的合并资源中进行，以及拉丁美洲，欧洲和非洲裔美国人亚组。将使用MCCAS中的类似结果和暴露复制结果。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起重要作用，从而找回部分缺失的哮喘遗传性。我们将确定重要的共享和种族 特定的基因-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.