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，是一种相互作用的复杂疾病