Multi-omic studies of asthma severity in an African ancestry population

非洲血统人群哮喘严重程度的多组学研究

• 批准号: 9522470
• 负责人: Kathleen C Barnes
• 金额: $ 75.01万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-02-01 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9522470
• 关键词: Affect; African; African Caribbean; Asthma; Barbados; Biological Process; CD4 Positive T Lymphocytes; Child; Complex; Control Locus; DNA; DNA Methylation; Data; Databases; Development; Disease; Environment; Environmental Exposure; Epidemic; Epigenetic Process; Epithelial; Epithelial Cells; Ethnic group; European; Extrinsic asthma; Family member; GALA; Gene Expression; Gene Expression Profile; Genes; Genetic; Genetic Determinism; Genetic Markers; Genetic Polymorphism; Genetic Transcription; Genetic Variation; Genetic study; Genomic DNA; Genomics; Genotype; Heritability; IgE; Lung; Measures; Mediating; Messenger RNA; Methylation; Molecular; Morphology; Nasal Epithelium; Nose; Parents; Participant; Pattern; Peripheral; Phenotype; Population; Predisposition; Process; Proteins; Public Health; Puerto Rico; Quantitative Trait Loci; RNA; Regulation; Regulatory Element; Research Infrastructure; Risk; Role; Sampling; Severities; Severity of illness; Signal Transduction; Single Nucleotide Polymorphism; Site; Stimulus; Technology; Testing; Transcript; Translating; Underrepresented Minority; United States National Institutes of Health; Untranslated RNA; Variant; Vulnerable Populations; airway epithelium; allergic airway inflammation; asthmatic; bronchial epithelium; cohort; disorder control; disorder risk; epigenome; gene environment interaction; genetic variant; genome sequencing; genome wide association study; methylation pattern; methylome; molecular sequence database; multiple omics; next generation sequencing; novel; parent grant; peripheral blood; phenotypic data; programs; recruit; response; transcriptome; transcriptome sequencing; transcriptomics; whole genome

Asthma disproportionately affects underrepresented minorities, and is a complex disease where the interplay between genetic factors and environmental exposures controls susceptibility. Airway epithelial cells are critical in the development of allergic airway inflammation, represent the first line of defense against environmental stimuli, and the nasal airway epithelium has been shown to mirror the bronchial epithelium morphologically and functionally. 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 nearly all of the asthma GWAS associations to date involve SNPs in intergenic or intronic regions, it seems likely that polymorphism markers in regulatory elements may account for a large portion of the missing heritability. It is also increasingly clear that epigenetic mechanisms may be causal for asthma, and studies suggest that SNPs are likely to affect both gene expression and methylation independently of one another; thus, both transcriptome and methylation data can independently be informative for defining functional genes. We recently completed whole genome sequencing (WGS) on 1,100 African Caribbean asthmatics and non- asthmatics, extensively phenotyped and followed participants for >20 years, living in a homogeneous, well- characterized environment, comprising the Barbados Asthma Genetics Study. Currently a subset is being recruited as part of the NIH-supported parent grant to characterize the transcriptome of peripheral blood CD4+ T cells, and perform an expression Quantitative Trait Locus (eQTL) study combining WGS and transcriptomic data. To test the hypothesis that genetic determinants confer risk to asthma, and expressed variation in the transcriptome and methylome of the nasal epithelium may mediate the relationship between genotype, phenotype and environment, we propose to integrate one of the most comprehensive WGS databases on an African ancestry population with next-generation sequencing technology (RNA-Seq) and eQTL mapping to elucidate how genetic variation controls differ in quantitative levels of gene expression of nasal airway epithelial cells. The specific aims of this application build upon the infrastructure of an ongoing program, and include the following: (i) identify cis- and trans-effects of variants identified in the transcriptome for isolated nasal epithelial cells from atopic asthmatics; (ii) identify eQTL patterns from nasal epithelial cells specific to atopic asthma; and (iii) identify DNA methylation changes associated with atopic asthma in the nasal airway epithelium, followed by an unbiased QTL analyses on the methylome (meQTL) and integrating novel eQTLs and meQTLs from transcript expression and methylation, respectively, to determine whether these QTLs identified in airway epithelial cells contribute to asthma risk. These studies should substantially advance our understanding of the molecular basis for asthma.

哮喘对代表性不足的少数群体造成不成比例的影响，并且是一种复杂的疾病，其中相互作用 遗传因素和环境暴露之间控制着易感性。气道上皮细胞至关重要 在过敏性气道炎症的发展过程中，代表着对抗环境的第一道防线 刺激，并且鼻气道上皮已被证明在形态上反映了支气管上皮 功能上。全基因组关联研究（GWAS）已成功识别相关基因 哮喘风险增加，但单核苷酸多态性 (SNP) 之间存在很大差距 GWAS 发现的关联并了解这些位点如何控制疾病。因为几乎所有的 迄今为止，哮喘 GWAS 关联涉及基因间或内含子区域的 SNP，看来很可能是 调控元件中的多态性标记可能是遗传性缺失的很大一部分原因。这是 人们也越来越清楚表观遗传机制可能是哮喘的病因，研究表明 SNP 可能相互独立地影响基因表达和甲基化；因此，两者 转录组和甲基化数据可以独立地为定义功能基因提供信息。我们 最近完成了对 1,100 名非洲加勒比哮喘患者和非哮喘患者的全基因组测序 (WGS) 哮喘患者，对参与者进行了广泛的表型分析并随访了 20 年以上，生活在同质、良好的环境中 特征环境，包括巴巴多斯哮喘遗传学研究。目前正在开发一个子集 作为 NIH 支持的家长资助的一部分招募来表征外周血 CD4+ 的转录组 T 细胞，并结合全基因组测序和转录组学进行表达定量性状基因座 (eQTL) 研究 数据。检验遗传决定因素赋予哮喘风险的假设，以及表达的变异 鼻上皮的转录组和甲基化组可能介导基因型之间的关系， 表型和环境，我们建议将最全面的 WGS 数据库之一整合到一个 利用新一代测序技术 (RNA-Seq) 和 eQTL 映射非洲血统人群 阐明遗传变异如何控制鼻气道基因表达定量水平的差异 上皮细胞。该应用程序的具体目标建立在正在进行的计划的基础设施之上，并且 包括以下内容：（i）鉴定转录组中鉴定的变体的顺式和反式效应 来自特应性哮喘患者的鼻上皮细胞； (ii) 从鼻上皮细胞中识别特定的 eQTL 模式 特应性哮喘； (iii) 识别与鼻气道特应性哮喘相关的 DNA 甲基化变化 上皮细胞，然后对甲基化组 (meQTL) 进行无偏 QTL 分析并整合新的 eQTL 和 meQTL 分别来自转录表达和甲基化，以确定这些 QTL 是否 在气道上皮细胞中发现的细菌会增加哮喘风险。这些研究将大大推进我们的 了解哮喘的分子基础。