Integrative Genomics in Asthmatics of African Descent

非洲裔哮喘的综合基因组学

• 批准号: 9244716
• 负责人: Kathleen C Barnes
• 金额: $ 80.18万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-12-01 至 2018-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9244716
• 关键词: Affect; African; African Caribbean; Alpha Cell; Area; Asthma; Barbados; Belief; Biological; Biological Assay; Biological Process; CD4 Positive T Lymphocytes; Characteristics; Child; Chronic; Clinical; Complement; Complex; Control Locus; Custom; DNA; Data; Databases; Development; Disease; Environment; Environmental Exposure; Environmental Risk Factor; Epidemic; European; Exposure to; Extrinsic asthma; Family member; Funding; Gene Expression; Gene Expression Profile; Genes; Genetic; Genetic Markers; Genetic Polymorphism; Genetic Transcription; Genetic Variation; Genome; Genomics; Genotype; Heritability; House Dust; IgE; Immune response; Individual; International; Measures; Messenger RNA; Methods; Mining; Minority Groups; Molecular; Participant; Pattern; Phenotype; Population; Predisposition; Prevalence; Public Health; Quantitative Trait Loci; RNA; Race; Regulatory Element; Research Infrastructure; Research Personnel; Risk; Sampling; Series; Severity of illness; Single Nucleotide Polymorphism; Source; Statistical Methods; Symptoms; T-Lymphocyte; T-Lymphocyte Subsets; Technology; Testing; Transcript; Underrepresented Minority; United States National Institutes of Health; Untranslated RNA; Variant; airway inflammation; asthmatic; cohort; design; disorder control; environmental allergen; genetic variant; genome wide association study; genome-wide; nano-string; next generation sequencing; novel; phenotypic data; public health relevance; response; trait; transcriptome; transcriptome sequencing

DESCRIPTION (provided by applicant): Asthma is a complex disease for which a strong genetic basis has been firmly established. Asthma prevalence is closely related to an immune response initiated by chronic exposure to certain environmental factors, especially those associated with house dust. Manifestations of asthma depend on T cell activities, particularly the CD4+ Th2 subset of T cells. Asthmatics of African ancestry 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 been successful in identifying genes associated with increased risk of asthma, but there is a substantial gap between single nucleotide polymorphism (SNP) associations discovered by GWAS and understanding how these loci control disease. Because most GWAS associations involve SNPs in intergenic or intronic regions, it seems likely polymorphisms in regulatory elements may account for a large portion of the missing heritability of asthma. To test this hypothesis, we propose a series of studies to integrate one of the most comprehensive GWAS databases on an African ancestry population with next-generation sequencing technology (RNA-Seq) and eQTL mapping, to elucidate the genetic variation underpinning differences in quantitative levels of gene expression of CD4+ T cells isolated from African Caribbean atopic asthmatics and non-atopic, non-asthmatic controls living in a homogeneous, well-characterized environment. This population from Barbados has been extensively phenotyped and followed for >20 years. The specific aims of this application build upon the infrastructure of an international group of investigators with diverse but highly integrated areas of expertise, and include the following: (i) to identify cis- and trans-effects of variants identified in the transcriptome from isolated CD4+ T cells from 250 atopic asthmatics by performing RNA-Seq followed by eQTL analyses; (ii) to identify eQTL patterns from CD4+ T cells specific to atopic asthma by comparing the transcriptomes of atopic asthmatics to that of 250 non-atopic, non-asthmatic controls, and explore regulatory networks associated with dysregulation of CD4+ T cells in asthma; and (iii) to integrate novel eQTLs among asthmatics (SA1) compared to non-asthmatics (SA2) with pre-existing asthma GWAS data. The strongest eQTLs will be validated by measuring the change in transcription in 150 independent atopic asthmatics and 150 non-atopic, non- asthmatic controls using NanoString nCounter technology. We will compare results generated from this study to publicly available eQTL data on CD4+ T cells from asthmatics and non-asthmatics generated from microarray assays to assess generalization, and explore networks of genes. By mining publicly available GWAS databases we will determine whether the novel eQTLs and transcript expression identified in CD4+ T cells contribute to asthma susceptibility and perhaps explain previously identified GWAS associations. These studies should substantially advance our understanding of the molecular basis for asthma.

描述（由申请人提供）：哮喘是一种复杂的疾病，已经确定了强大的遗传基础。哮喘患病率与长期暴露于某些环境因素（尤其是与房屋灰尘相关的环境因素）引发的免疫反应密切相关。哮喘的表现取决于T细胞活性，尤其是T细胞的CD4+ TH2子集。与欧洲血统的人相比，非洲血统的哮喘患者往往具有更严重的哮喘和更严重的临床症状，但相对较少的研究集中在这个代表性不足的少数群体上。全基因组关联研究（GWAS）已成功地识别与哮喘风险增加有关的基因，但是GWAS发现的单核苷酸多态性（SNP）关联之间存在很大的差距，并了解这些基因座控制疾病如何。由于大多数GWAS关联都涉及基因间或内含子区域中的SNP，因此调节元素中的多态性似乎可能占缺失哮喘的遗传力的很大一部分。为了检验这一假设，我们提出了一系列研究，以将非洲血统的最全面的GWAS数据库与下一代测序技术（RNA-SEQ）（RNA-SEQ）（RNA-SEQ）和EQTL映射整合在一起，以阐明遗传变异在非洲+ T细胞中的定量差异差异，从居住在均匀，良好的环境中的非心律控制。来自巴巴多斯的这个人口已被广泛表现出来，遵循了20年。该申请的具体目的是建立在具有多样化但高度集成专业领域的国际调查人员的基础设施上，并包括以下内容：（i）确定顺式和变形 通过进行RNA-Seq，然后进行EQTL分析，从250个特应性哮喘的分离的CD4+ T细胞中鉴定出的变体。 （ii）通过将特应性哮喘的转录组与250种非原子，非亚种子控制的转录组进行比较，并探索与哮喘中CD4+ T细胞失调相关的调节网络，从而鉴定从CD4+ T细胞中的EQTL模式。 （iii）将新颖的EQTL与非亚第Asthmatics（SA2）（SA2）与先前存在的哮喘GWAS数据相比。最强的EQTL将通过测量150种独立特应性哮喘患者的转录变化和150种非原子，非哮喘控制的转录变化来验证。我们将将这项研究产生的结果与来自微阵列分析产生的哮喘患者和非偶像的CD4+ T细胞的公开可用的EQTL数据，以评估概括并探索基因网络。通过挖掘公开可用的GWAS数据库，我们将确定在CD4+ T细胞中鉴定的新型EQTL和转录本表达是否有助于哮喘敏感性，也许可以解释先前确定的GWAS关联。这些研究应大大提高我们对哮喘分子基础的理解。