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: 8054694
• 负责人: Kathleen C Barnes
• 金额: $ 255.63万
• 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/8054694
• 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. PUBLIC HEALTH RELEVANCE: In this study we will take advantage of discoveries in the 1000 Genomes Project and select genetic variants that best represent the genome of individuals of African descent. We will use this information to develop a custom "SNP" chip (called the African Power Chip) to complement current, commercially available chips, and identify genetic polymorphisms associated with risk of asthma in DNA samples from 12,000 individuals.

描述（由申请人提供）：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具有显着影响。与欧洲血统的个体相比，非洲裔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性不足的少数群体。全基因组关联研究 (GWAS) 彻底改变了多种复杂性状的基因发现，但在非洲人后裔人群中进行哮喘 GWAS 后，基因发现的下一步实施需要考虑该种族群体特有的因素，包括足够的样本量、由于混合而进行的人群分层，也许最重要的是，采用一种方法，认识到当前公共数据库和特别是商业上可用的 SNP 中常见变异的覆盖范围 芯片不足以检测非洲混合人群之间真正的遗传关联。在我们对来自巴尔的摩-华盛顿特区的 1,000 名非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进行的 GWAS 中，我们发现了在欧洲血统人群中未观察到复制的提示性关联，支持了非洲血统人群可能携带独特易感基因座的假设。我们与代表来自特征明确的非裔美国人和非洲加勒比哮喘患者以及健康对照和/或家庭成员的 12,000 个 DNA 样本的研究人员建立了合作关系，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（>7,000 个样本）可用于复制。在此应用中，我们提出了四个具体目标：(i) 我们将利用千基因组计划的发现以及非洲和非洲混合人群中新型 SNP 的数据挖掘，开发定制的、以非洲血统基因为中心的 200K SNP 基因分型阵列（“非洲 Power Chip”），以补充当前市售的 GWAS 芯片，现有 SNP 无法充分标记常见和罕见的变异， 从而促进对非洲人后裔群体的 GWAS 研究； (ii) 我们将利用“美洲非洲裔哮喘联盟”(CAAPA) 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，然后； (iii) 深入分析，包括基于插补的哮喘基因座关联图谱、拷贝数变异（CNV）分析和混合图谱； (iv) 在通过 CAAPA 获得的独立样本中复制最显着的关联。这些研究的结果将带来技术的重大进步，用于识别与生物医学研究中代表性最不足的少数群体之一、非洲血统人群的疾病相关的基因，并将为整个科学界提供成果，既作为宝贵的数据库，又作为经过验证的 SNP 芯片。 公共卫生相关性：在这项研究中，我们将利用千人基因组计划的发现，选择最能代表非洲人后裔基因组的​​遗传变异。我们将利用这些信息开发定制的“SNP”芯片（称为非洲功率芯片），以补充现有的商用芯片，并在 12,000 名个体的 DNA 样本中识别与哮喘风险相关的遗传多态性。