The Airway Functional Genomics of Bronchodilator Drug Response in Minority Children with Asthma

少数民族哮喘儿童支气管扩张剂药物反应的气道功能基因组学

• 批准号: 9889982
• 负责人: Nadav Ahituv
• 金额: $ 79.1万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9889982
• 关键词: Acute; African American; Agonist; Air; Albuterol; American; Asthma; Biological Assay; Bronchodilator Agents; CRISPR/Cas technology; Cells; ChIP-seq; Child; Chromatin; Chromatin Structure; Chronic; Chronic Disease; Clinical Data; Collaborations; Complex; Data; Death Rate; Dose; Encyclopedias; Enhancers; Epithelial Cells; Ethnic Origin; Exhibits; Funding; Gene Expression; Gene Targeting; Genes; Genetic; Genetic Transcription; Genome; Genomics; Goals; Health Policy; Heritability; Knowledge; Laboratories; Lead; Liquid substance; Low income; Lung diseases; Mexican; Mexican Americans; Minority; Modification; Morbidity - disease rate; Nose; Nucleic Acid Regulatory Sequences; Pathway interactions; Patients; Pattern; Pharmaceutical Preparations; Pharmacogenetics; Pharmacogenomics; Phenotype; Play; Population; Populations at Risk; Prevalence; Public Health; Puerto Rican; Quantitative Trait Loci; Race; Recording of previous events; Regulator Genes; Regulatory Element; Research; Role; Severities; Signal Transduction; Stimulus; System; Testing; Transposase; Untranslated RNA; Validation; Variant; Work; airway epithelium; airway inflammation; asthmatic; base; bronchial epithelium; cell type; clinical practice; differential expression; epigenomics; ethnic difference; ethnic diversity; follow-up; frontier; functional genomics; genome sequencing; genome wide association study; genome-wide; genomic data; genomic locus; improved; insight; minority children; mortality; multiple omics; racial and ethnic; racial and ethnic disparities; racial difference; rare variant; respiratory smooth muscle; response; targeted treatment; transcriptome; transcriptome sequencing; whole genome

ABSTRACT Asthma is the most common chronic disease among children. Asthma prevalence, mortality, and drug response vary by race/ethnicity and genetic ancestry. In the U.S., asthma prevalence is highest among Puerto Ricans (36.5%), intermediate among African Americans (13.0%) and whites (12.1%), and lowest in Mexicans (7.5%). These disparities extend to asthma mortality, which is four-fold higher in Puerto Ricans and African Americans compared to Mexican Americans. Albuterol is the most commonly prescribed asthma medication in the world and is the mainstay of acute asthma management. Among low income and minority populations in the U.S., albuterol is often the only medication used regardless of asthma severity. Poor drug response contributes to racial/ethnic disparities in asthma morbidity and mortality. Disturbingly, Americans with the highest asthma prevalence and death rate also have the lowest drug response. Chronic albuterol use can decrease acute airway smooth muscle response to albuterol and increase airway inflammation through beta-agonist signaling in the airway epithelium, suggesting that chronic albuterol use may alter acute response through genomic and epigenomic modification of airway cells. Furthermore, acute bronchodilator drug response (BDR) to albuterol is a complex phenotype with an estimated heritability of 28.5%, indicating genetic factors contribute to BDR variability. Genome-wide and whole genome association analyses have revealed population-specific common and rare variants in non-coding regions of the genome associated with the extremes of BDR. The roles of genomic regulatory regions and population-specific variants in BDR have yet to be fully investigated. To this end, we have created an investigative system involving airway-specific cell types, patient-derived cells, and detailed clinical data to generate an encyclopedia of genes, regulatory regions, and pathways involved in BDR to albuterol. We will integrate RNA-seq, ChIP-seq, ATAC-seq, and whole genome sequencing data with detailed clinical data to identify trans-ethnic and population-specific variants contributing to differential expression and chromatin structure patterns in response to albuterol exposure. Furthermore, we will functionally characterize the regulatory regions that underlie acute and chronic albuterol BDR in multi-ethnic children with asthma using CRISPR-Cas9 activation/inhibition assays. These analyses will allow us to determine on a genomic scale the functional consequences of acute and chronic albuterol treatment on airway cells, and provide insight into potential targetable genes, regulatory elements, and pathways for improved asthma therapies in at-risk populations.

摘要 哮喘是儿童中最常见的慢性疾病。哮喘患病率、死亡率和药物 反应因种族/民族和遗传祖先而异。在美国，哮喘患病率在波多黎各最高， 波多黎各人（36.5%），非洲裔美国人（13.0%）和白人（12.1%）居中，墨西哥人最低 (7.5%).这些差异延伸到哮喘死亡率，这是四倍高，在波多黎各和非洲 与墨西哥裔美国人相比。沙丁胺醇是美国最常用的哮喘药物 是急性哮喘管理的支柱。在低收入和少数民族人口中， 美国，无论哮喘的严重程度如何，沙丁胺醇通常是唯一使用的药物。不良的药物反应 哮喘发病率和死亡率的种族/民族差异。令人不安的是，美国人的哮喘最高 流行率和死亡率也是药物反应最低的。慢性沙丁胺醇使用可减少急性 气道平滑肌对沙丁胺醇的反应，并通过β-激动剂信号传导增加气道炎症 在气道上皮中，表明慢性沙丁胺醇使用可能通过基因组和 气道细胞的表观基因组修饰。此外，对沙丁胺醇的急性支气管扩张药物反应（BDR） 一个复杂的表型，估计遗传率为28.5%，表明遗传因素有助于BDR 可变性全基因组和全基因组关联分析显示， 以及与BDR极端相关的基因组非编码区的罕见变异。的作用 BDR中的基因组调控区和群体特异性变体尚未被充分研究。本 最后，我们建立了一个研究系统，涉及气道特异性细胞类型，患者来源的细胞， 详细的临床数据，以生成涉及BDR的基因、调控区域和途径的百科全书 沙丁胺醇我们将整合RNA-seq，ChIP-seq，ATAC-seq和全基因组测序数据， 详细的临床数据，以确定跨种族和人群特异性变异， 表达和染色质结构模式。此外，我们将 功能特征的调节区域，急性和慢性沙丁胺醇BDR的基础上，在多种族 使用CRISPR-Cas9激活/抑制测定的哮喘儿童。这些分析将使我们能够确定 在基因组水平上急性和慢性沙丁胺醇治疗对气道细胞的功能影响， 深入了解改善哮喘的潜在靶向基因、调节元件和途径 治疗高危人群。