Integrative Genomics in Asthmatics of African Descent

非洲裔哮喘的综合基因组学

• 批准号: 9230688
• 负责人: Kathleen C Barnes
• 金额: $ 50.4万
• 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/9230688
• 关键词: Accounting; Affect; African; African Caribbean; Area; Asthma; Barbados; Belief; Biological; Biological Assay; Biological Process; CD4 Positive T Lymphocytes; Cells; 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; Life; Maps; 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; base; cohort; data mining; design; disorder control; environmental allergen; genetic variant; genome wide association study; genome-wide; nano-string; next generation sequencing; novel; 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，其强大的遗传基础已经牢固确立。哮喘的发病率与长期暴露于某些环境因素，特别是与室内灰尘有关的环境因素引起的免疫反应密切相关。哮喘的表现取决于T细胞活性，特别是T细胞的CD 4 + Th 2亚群。与欧洲血统的个体相比，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，但相对较少的研究关注这一代表性不足的少数群体。全基因组关联研究（GWAS）已经成功地鉴定了与哮喘风险增加相关的基因，但GWAS发现的单核苷酸多态性（SNP）关联与理解这些基因座如何控制疾病之间存在很大差距。由于大多数GWAS关联涉及基因间或内含子区域的SNP，因此调节元件的多态性可能是哮喘遗传性缺失的主要原因。为了验证这一假设，我们提出了一系列研究，将非洲血统人群中最全面的GWAS数据库之一与下一代测序技术（RNA-Seq）和eQTL定位相结合，以阐明从非洲加勒比地区特应性哮喘患者和非特应性非哮喘对照中分离的CD 4 + T细胞基因表达定量水平差异的遗传变异，特色鲜明的环境。来自巴巴多斯的这一人群已被广泛分型，并被跟踪超过20年。这项申请的具体目的是建立在一个具有不同但高度综合的专门知识领域的国际调查小组的基础上，包括： （ii）通过比较特应性哮喘患者的转录组与250个非特应性、非哮喘对照的转录组，鉴定来自特应性哮喘特异性的CD 4 + T细胞的eQTL模式，并探索与哮喘中CD 4 + T细胞失调相关的调节网络;和（iii）整合哮喘患者（SA 1）与非哮喘患者（SA 2）之间的新eQTL与预先存在的哮喘GWAS数据。最强的eQTL将通过使用NanoString nCounter技术测量150名独立的特应性哮喘患者和150名非特应性、非哮喘对照中的转录变化来验证。我们将比较本研究产生的结果与公开可用的eQTL数据，这些数据来自哮喘患者和非哮喘患者的CD 4 + T细胞，这些数据来自微阵列检测，以评估泛化，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CD 4 + T细胞中鉴定的新eQTL和转录表达是否有助于哮喘易感性，并可能解释先前鉴定的GWAS关联。这些研究将大大促进我们对哮喘分子基础的理解。