New Approaches for Empowering Studies of Asthma in Populations of African Descent

非洲人后裔哮喘研究的新方法

• 批准号: 8338759
• 负责人: Kathleen C Barnes
• 金额: $ 239.23万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-28 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8338759
• 关键词: Accounting; Admixture; Affect; African; African American; African Caribbean; Americas; Area; Asthma; Baltimore; Barbados; Biomedical Research; Characteristics; Child; Clinical; Collaborations; Communities; Complement; Complex; Copy Number Polymorphism; Custom; DNA; Data; Data Analyses; Data Set; Databases; Disease; Disease Progression; Disease susceptibility; District of Columbia; Environmental Exposure; Epidemic; Ethnic group; European; Family member; Genes; Genetic; Genetic Polymorphism; Genome; Genome Scan; Genotype; Goals; Grant; IgE; Individual; Institution; International; Lead; Linkage Disequilibrium; Maps; Meta-Analysis; Minority Groups; Molecular Genetics; National Heart, Lung, and Blood Institute; Population; Population Genetics; Population Heterogeneity; Predisposition; Public Health; Research Personnel; Risk; SNP genotyping; Sample Size; Sampling; Stratification; Susceptibility Gene; Symptoms; Technology; Testing; Underrepresented Minority; Variant; asthmatic patient; base; case control; data mining; density; empowered; follow-up; forging; gene discovery; genetic association; genetic epidemiology; genetic variant; genome wide association study; genome-wide; markov model; metropolitan; novel; novel strategies; outcome forecast; sample collection; trait

DESCRIPTION (provided by applicant): Asthma is a complex disease where the interplay between genetic factors and environmental exposures has significant influence on susceptibility and disease prognosis. Asthmatics of African descent tend to have more severe asthma and more severe clinical symptoms than individuals of European ancestry, but relatively few studies have focused on this underrepresented minority group. Genome-wide association studies (GWAS) have revolutionized gene discovery for multiple complex traits, but implementation of the next step in gene discovery following GWAS of asthma among populations of African descent requires considerations unique to this ethnic group, including adequate sample sizes, population stratification due to admixture, and perhaps most importantly, an approach that recognizes that the current coverage of common variation both in the public database and particularly on commercially available SNP chips is inadequate to detect true genetic association among African admixed populations. In our own GWAS on 1,000 African American asthma cases and controls from Baltimore-Washington, D.C. and 1,000 African Caribbean asthmatics and their family members from Barbados, we have identified suggestive associations for which replication is not observed in populations of European descent, supporting the hypothesis that populations of African descent may carry unique susceptibility loci. We have forged a collaboration of investigators representing 12,000 DNA samples from well-characterized African American and African Caribbean asthmatic patients and healthy controls and/or family members from which six studies (5,000 samples) have GWAS data available for meta-analysis and seven populations (>7,000 samples) are available for replication. In this application, we propose four specific aims: (i) we will leverage discoveries in the 1,000 Genomes Project and data-mine for novel SNPs in African and African admixed populations develop a custom, African-ancestry gene-centric 200K SNP genotyping array ('African Power Chip') to complement current, commercially available GWAS chips, for which common and rare variants are not adequately tagged by the existing SNPs, and thereby facilitate GWAS studies on populations of African descent; (ii) we will perform genotyping on DNA samples with existing GWAS data among the 'Consortium on Asthma among African-ancestry Populations in the Americas' (CAAPA) and test for associations with asthma, followed by; (iii) in-depth analyses including imputation-based association mapping of asthma loci, copy number variant (CNV) analyses, and admixture mapping; and (iv) replicate the most significant associations in independent samples available through CAAPA. Results from these studies will lead to substantial advancements in the technology available for identifying genes relevant to disease for what is one of the most underrepresented minorities in biomedical research, African ancestry populations, and will generate deliverables to the scientific community at large, both as an invaluable database and as a validated SNP chip.

描述(申请人提供)：哮喘是一种复杂的疾病，遗传因素和环境暴露之间的相互作用对易感性和疾病预后有重大影响。与欧洲血统的人相比，非洲人后裔的哮喘患者往往患有更严重的哮喘和更严重的临床症状，但相对较少的研究关注这一代表不足的少数群体。全基因组关联研究使多种复杂性状的基因发现发生了革命性变化，但在非洲裔人群哮喘的全基因组关联研究之后的下一步基因发现的实施需要考虑这一族群特有的因素，包括足够的样本量、由于混合而造成的群体分层，也许最重要的是，一种认识到目前公共数据库中的共同变异的覆盖率，特别是商业上可获得的SNP芯片的方法，不足以检测非洲混合人群中真正的遗传关联。在我们自己对来自巴尔的摩-华盛顿特区的1,000名非洲裔美国人哮喘病例和对照以及来自巴巴多斯的1,000名非洲加勒比哮喘患者及其家人的GWA中，我们发现了一些具有启发性的关联，这些关联在欧洲裔人群中没有观察到，这支持了非洲裔人群可能携带独特易感基因的假设。我们已经建立了一个代表12,000个DNA样本的研究人员协作，这些样本来自特征良好的非裔美国人和非洲加勒比哮喘患者和健康对照和/或家庭成员，其中6项研究(5,000个样本)具有可用于荟萃分析的Gwas数据，7个人群(&gt；7,000个样本)可用于复制。在这项申请中，我们提出了四个具体目标：(I)我们将利用1000基因组计划和数据挖掘中在非洲和非洲混合人群中新的SNP的发现，开发一个定制的、以非洲血统基因为中心的200K SNP基因分型芯片(‘African Power Chip’)，以补充现有商业上可用的GWAS芯片，现有的SNP不能充分标记常见和稀有变体，从而促进GWAS对非洲裔人口的研究；(Ii)我们将利用‘美洲非洲裔人群哮喘联合会’(CAAPA)中现有的Gwas数据对DNA样本进行基因分型，并测试与哮喘的关联，随后进行；(Iii)深入分析，包括哮喘基因座的基于归因的关联图谱、拷贝数变异(CNV)分析和混合图谱；以及(Iv)在通过CAAPA获得的独立样本中复制最重要的关联。这些研究的结果将导致现有技术的重大进步，以便为生物医学研究中代表性最低的少数群体--非洲人后裔--确定与疾病有关的基因，并将产生交付给整个科学界的成果，既是一个宝贵的数据库，也是一个经过验证的SNP芯片。