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<$2-激动剂，是世界上最常用的哮喘药物。不同种族和民族之间对沙丁胺醇的治疗反应存在显著差异。我们证明了波多黎各和非洲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的儿童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，具有潜在的更大的影响大小比常见的SNP，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：对少数哮喘儿童中支气管扩张剂反应（BDR）的极端表型进行“Exome Plus”DNA测序。将选择总计1500名患有哮喘和极端药物反应表型的少数民族儿童进行测序，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，靶捕获探针组被设计为捕获人外显子（38 Mb）、>1000个非编码RNA和6 Mb的定制序列。我们将把“Plus”测序的重点放在鉴定气道平滑肌细胞中表达的2,153个候选基因的顺式调节变体和我们自己的GWAS结果上。具体目标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合并变异进行关联性检验，并在一个大型独立的拉丁裔和非洲裔美国人哮喘受试者组（n= 2，235）中检验最高命中与BDR的关联性。然后，我们将在另外4，980人中复制我们的发现。具体目标3：确定与支气管扩张剂反应相关的启动子变体是否导致原代气道平滑肌细胞中的差异基因表达。我们已经开发了基于染色质的启动子报告基因测定，其将提供用于高通量研究非编码和启动子变体的下一代系统，所述非编码和启动子变体被认为在人类疾病和药物应答中如此重要。

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.