Pharmacogenomics of Bronchodilator Response in Minority Children with Asthma

描述（由申请人提供）：沙丁胺醇是一种短效激动剂，是世界上最常用的哮喘药物。不同种族和民族对沙丁胺醇的治疗反应有显著差异。我们证明了波多黎各和非裔美国哮喘儿童对沙丁胺醇的反应明显低于墨西哥儿童。我们的目标是了解不同儿科哮喘人群中不同药物反应的生物学基础。我们假设罕见的外显子和启动子变异，可能比常见的snp具有更大的效应大小，有助于沙丁胺醇反应的种族/民族差异。我们将用三个具体目标来检验我们的假设。具体目标1：对少数民族哮喘儿童支气管扩张剂反应（BDR）的极端表型进行“Exome Plus”DNA测序。共有1500名患有哮喘和极端药物反应表型的少数民族儿童将被选择进行测序，包括波多黎各人（n=500），墨西哥人（n=500）和非洲裔美国人（n=500）。使用“Exome-Plus”方法，目标捕获探针集被设计用于捕获人类外显子（38 Mb）， bb1000个非编码rna和6 Mb的自定义序列。我们将把“Plus”测序的重点放在鉴定2,153个候选基因中的顺式调控变异，这些基因被鉴定为在气道平滑肌细胞中表达，并获得我们自己的GWAS结果。特异性目标2：确定与支气管扩张剂反应相关的遗传变异。我们将在发现阶段（n=1500）对高和低药物应答者之间的个体和集合变异进行关联测试，并在大型独立的拉丁裔和非裔美国哮喘患者组（n= 2235）中测试最热门药物与BDR之间的关联。然后，我们将在另外4,980个人身上重复我们的发现。特异性目的3：确定与支气管扩张剂反应相关的启动子变异是否会导致初级气道平滑肌细胞的差异基因表达。我们已经开发了一种基于染色质的启动子报告试验，将为非编码和启动子变体的高通量研究提供下一代系统，这些变体被认为在人类疾病和药物反应中非常重要。

DESCRIPTION (provided by applicant): Albuterol, a short-acting ¿2-agonist, is the most commonly prescribed asthma medication in the world. There are marked differences in the therapeutic response to albuterol between racial and ethnic groups. We demonstrated that Puerto Rican and African American children with asthma were significantly less responsive to albuterol than Mexican children. Our goal is to understand the biological basis of differential drug response in diverse pediatric populations with asthma. We hypothesize that rare exonic and promoter variants, with potentially larger effect sizes than common SNPs, contribute to racial/ethnic differences in albuterol response. We will test our hypothesis with three specific aims. Specific Aim 1: Perform "Exome Plus" DNA sequencing on extreme phenotypes of bronchodilator response (BDR) among minority children with asthma. A total of 1500 minority children with asthma and extreme drug response phenotypes will be selected for sequencing, including Puerto Ricans (n=500), Mexicans (n=500) and African Americans (n=500). With the "Exome-Plus" approach, the target capture probe set is designed to capture human exons (38 Mb), >1000 non-coding RNAs, and 6 Mb of custom sequences. We will focus the "Plus" sequencing on the identification of cis-regulatory variants in a set of 2,153 candidate genes identified as being expressed in airway smooth muscle cells and our own GWAS results. Specific Aim 2: Identify genetic variation associated with bronchodilator response. We will perform association testing on individual and pooled variants between high and low drug responders in the discovery phase (n=1500), and test for an association of the top hits with BDR in a large, independent group of Latino and African American subjects with asthma (n=2,235). We will then replicate our findings in an additional 4,980 individuals. Specific Aim 3: Determine whether promoter variants associated with bronchodilator response cause differential gene expression in primary airway smooth muscle cells. We have developed a chromatin based promoter reporter assay that will provide a next-generation system for the high- throughput study of non-coding and promoter variants believed to be so important in human disease and drug response.