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: 10331294
• 负责人: Kathleen C Barnes
• 金额: $ 66.08万
• 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 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10331294
• 关键词: Affect; African Caribbean; African ancestry; Asthma; Barbados; Biological Process; Blood Cells; CD4 Positive T Lymphocytes; Child; Complex; Control Locus; DNA; DNA Methylation; Data; Databases; Development; Disease; Environment; Environmental Exposure; Epidemic; Epigenetic Process; Epithelial Cells; Ethnic group; European; Extrinsic asthma; Family member; GALA; Gene Expression; Gene Expression Profile; Gene set enrichment analysis; Genes; Genetic; Genetic Determinism; Genetic Markers; Genetic Polymorphism; Genetic Transcription; Genetic Variation; Genetic study; Genomic DNA; Genotype; Heritability; IgE; Infrastructure; Lung; Measures; Mediating; Messenger RNA; Methylation; Molecular; Morphology; Multiomic Data; Nasal Epithelium; Nose; Parents; Participant; Pattern; Peripheral; Phenotype; Population; Predisposition; Process; Proteins; Public Health; Puerto Rico; Quantitative Trait Loci; RNA; Regulation; Regulatory Element; 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; genomic data; methylation pattern; methylome; molecular sequence database; multiple omics; next generation sequencing; novel; parent grant; peripheral blood; phenotypic data; programs; recruit; transcriptome; transcriptome sequencing; transcriptomics; treatment response; 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.

哮喘不成比例地影响代表性不足的少数民族，并且是一种复杂的疾病， 遗传因素和环境暴露之间的联系控制了易感性。气道上皮细胞是至关重要的 在过敏性气道炎症的发展中，代表了对抗环境的第一道防线。 刺激，并且鼻气道上皮已经显示出在形态上反映支气管上皮， 功能上。全基因组关联研究（GWAS）已经成功地鉴定了与基因表达相关的基因。 哮喘的风险增加，但单核苷酸多态性（SNP） GWAS发现的关联，并了解这些基因座如何控制疾病。因为几乎所有的 迄今为止，哮喘GWAS的关联涉及基因间或内含子区域的SNP， 调节元件中的多态性标记可能占缺失遗传力的很大一部分。是 表观遗传机制可能是哮喘的病因，研究表明， 可能会相互独立地影响基因表达和甲基化;因此， 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，广泛的表型，并跟踪参与者>20年，生活在一个同质的，良好的， 巴巴多斯哮喘遗传学研究（Barbados Asthma Genetics Study）目前，一个子集正在 作为NIH支持的父母资助的一部分招募，以表征外周血CD 4+的转录组 T细胞，并进行结合WGS和转录组学的表达定量性状基因座（eQTL）研究。 数据为了验证遗传决定因素与哮喘风险有关的假设， 鼻上皮的转录组和甲基化组可能介导基因型， 表型和环境，我们建议整合一个最全面的WGS数据库上， 利用下一代测序技术（RNA-Seq）和eQTL作图， 阐明遗传变异控制如何在鼻气道基因表达的定量水平上有所不同 上皮细胞本申请的具体目标建立在正在进行的项目的基础设施之上， 包括以下内容：（i）鉴定在分离的转录组中鉴定的变体的顺式和反式效应， （ii）从特异性哮喘患者的鼻上皮细胞鉴定eQTL模式， 特应性哮喘;和（iii）鉴定鼻气道中与特应性哮喘相关的DNA甲基化变化 上皮细胞，然后对甲基化组（meQTL）和整合新的eQTL进行无偏QTL分析 和meQTL，分别从转录表达和甲基化，以确定这些QTL 在气道上皮细胞中发现的基因与哮喘风险有关。这些研究将大大促进我们的 了解哮喘的分子基础。