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族裔，这是一种复杂的疾病，其中相互作用 在遗传因素和环境暴露之间控制易感性。气道上皮细胞很关键 在过敏性气道炎症的发展中，代表了针对环境的第一道防线 刺激和鼻气道上皮已被证明可以在形态和 在功能上。全基因组关联研究（GWAS）已成功地识别相关的基因 随着哮喘的风险增加，但单核苷酸多态性（SNP）之间存在很大的差距 GWAS发现的协会并了解了这些基因座控制疾病。因为几乎所有 迄今 监管元素中的多态性标志物可能占缺失遗传力的很大一部分。这是 同样越来越清楚的表观遗传机制可能是哮喘的原因，研究表明SNP 可能独立于彼此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1,100次非洲加勒比海哮喘患者和非 - 的全基因组测序（WGS） 哮喘患者广泛表现出来，并跟随参与者超过20年，生活在同质，良好的 表征环境，包括巴巴多斯哮喘遗传学研究。目前正在一个子集 作为NIH支持的父母赠款的一部分招募，以表征外周血CD4+的转录组 T细胞，并执行结合WGS和转录组的表达定量性状基因座（EQTL）研究 数据。测试遗传决定因素赋予哮喘风险的假设，并表达了差异 鼻上皮的转录组和甲基甲基体可以介导基因型， 表型和环境，我们建议将最全面的WGS数据库之一整合在 具有下一代测序技术（RNA-SEQ）和EQTL映射的非洲血统人群 阐明遗传变异控制如何在鼻气道的基因表达的定量水平上有所不同 上皮细胞。本申请的具体目的是建立在正在进行的计划的基础架构上的，并且 包括以下内容：（i）识别在转录组中鉴定出的变体的顺式和转移效应 来自特应性哮喘患者的鼻皮细胞； （ii）从特异性的鼻皮细胞中确定EQTL模式 特应哮喘； （iii）确定与鼻气道中特应性哮喘相关的DNA甲基化变化 上皮，然后对甲基组（MEQTL）进行公正的QTL分析，并整合了新型EQTL 分别来自转录本表达和甲基化的MEQTL，以确定这些QTL是否是否 在气道上皮细胞中确定有助于哮喘风险。这些研究应该大大推动我们的 了解哮喘的分子基础。