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: 9256781
• 负责人: Kathleen C Barnes
• 金额: $ 74.8万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-17 至 2017-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9256781
• 关键词: New; Approaches; Empowering; Studies; Asthma

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.

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具有 对易感性和疾病预后的重大影响。非洲血统的哮喘患者往往有更多 与欧洲血统的人相比，严重的哮喘和更严重的临床症状，但相对较少 研究的重点是这个代表性不足的少数群体。全基因组关联研究（GWAS） 已经彻底改变了多个复杂特征的基因发现，但实施了基因的下一步 在非洲血统人群中发现GWA的哮喘之后的发现需要 这个种族，包括足够的样本数量，由于混合而导致的人口分层，也许 最重要的是，这种方法认识到当前对公众的共同变化的覆盖范围 数据库，尤其是在市售的SNP芯片上不足以检测真正的遗传关联 在非洲混杂人群中。在我们自己的1,000名非裔美国人哮喘病例和对照的GWA中 来自巴尔的摩 - 华盛顿特区和1,000名非洲加勒比海哮喘患者及其家人 巴巴多斯，我们已经确定了暗示性的关联 欧洲血统，支持以下假设，即非洲血统可能具有独特 敏感位点。我们已经建立了一个调查人员的合作，代表12,000个DNA样本 特征良好的非洲裔美国人和非洲加勒比海哮喘患者和健康对照组和/或 六项研究（5,000个样本）的家庭成员可用于荟萃分析和 有7个人群（> 7,000个样本）可供复制。在此应用中，我们提出了四个特定的 目的：（i）我们将利用1000个基因组项目和非洲新颖SNP的数据矿山的发现 和非洲混合种群发展了一种习俗，非洲 - 官员基因以200k为中心的200k SNP基因分型阵列 （“非洲力量芯片”）以补充市场可用的GWAS芯片，以便于此 现有SNP并没有充分标记稀有变体，从而促进了GWAS的研究 非洲血统的种群； （ii）我们将对具有现有GWAS数据的DNA样品进行基因分型 在“美洲非洲裔人口中的哮喘联盟”（CAAPA）和测试中 与哮喘的关联，其次是； （iii）深入分析，包括基于插补的关联映射 哮喘基因座，拷贝数变体（CNV）分析和混合映射； （iv）复制最多 通过CAAPA获得的独立样本中的显着关联。这些研究的结果将导致 在可用的技术中取得了重大进步，以识别与疾病相关的基因 非洲血统人群中人物最多的少数群体之一，将 作为一个宝贵的数据库和经过验证 SNP芯片。