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

摘要 哮喘是儿童中最常见的慢性病。哮喘患病率、死亡率和药物 反应因种族/民族和遗传血统而异。在美国，哮喘患病率在波多黎各最高 里亚裔(36.5%)，非裔美国人(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，波多黎各人和非洲人的哮喘死亡率高出四倍 美国人和墨西哥人相比。沙丁胺醇是#年最常用的哮喘药物。 是世界上哮喘急性治疗的中流砥柱。在中国的低收入和少数民族人口中 在美国，沙丁胺醇通常是唯一使用的药物，无论哮喘严重程度如何。不良的药物反应是原因之一 在哮喘发病率和死亡率方面存在种族/族裔差异。令人不安的是，哮喘程度最高的美国人 患病率和死亡率也是药物反应最低的。长期使用沙丁胺醇可降低急性发作 气道平滑肌对沙丁胺醇的反应及通过β-受体激动剂信号转导增加气道炎症 提示长期使用沙丁胺醇可能通过基因组和基因改变急性反应。 呼吸道细胞的表观基因组修饰。此外，沙丁胺醇的急性支气管扩张剂药物反应(BDR)是 复杂的表型，估计遗传力为28.5%，表明遗传因素对BDR有贡献 可变性。全基因组和全基因组关联分析揭示了群体特有的共同 以及与BDR极端相关的基因组非编码区的罕见变异。的角色 BDR的基因组调控区和群体特异性变异尚未得到充分的研究。对这件事 最后，我们创建了一个涉及呼吸道特定细胞类型、患者来源的细胞和 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。我们将把RNA-SEQ、CHIP-SEQ、ATAC-SEQ和全基因组测序数据与 详细的临床数据以确定导致差异的跨种族和特定于人群的变异 沙丁胺醇暴露后的表达和染色质结构模式。此外，我们还将 多种族急性和慢性沙丁胺醇BDR背后的调节区域的功能特征 应用CRISPR-Cas9激活/抑制试验检测哮喘儿童。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呼吸道细胞的功能后果，以及 洞察潜在的靶向基因、调节元件和改善哮喘的途径 高危人群中的治疗方法。

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.