Pharmacogenomics of Bronchodilator Response in Minority Children with Asthma

少数民族哮喘儿童支气管扩张剂反应的药物基因组学

• 批准号: 8708960
• 负责人: Esteban Gonzalez Burchard
• 金额: $ 70.47万
• 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 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8708960
• 关键词: Acute; African American; Agonist; Albuterol; Area; Asthma; Automobile Driving; Biological; Biological Assay; Bronchodilation; Bronchodilator Agents; CCL4 gene; Candidate Disease Gene; Cells; Child; Childhood; Chromatin; Custom; DNA Resequencing; DNA Sequence; Data Set; Dependovirus; Ethnic Origin; Ethnic group; European; Exons; Flow Cytometry; Frequencies; Functional RNA; Future; Gene Expression; Gene Frequency; Genetic; Genetic Variation; Genome; Genotype; Goals; Health Policy; Human; Human Genome; Individual; Latino; Lead; Low income; Measures; Mexican; Minor; Minority; Minority Groups; Morbidity - disease rate; Nucleic Acid Regulatory Sequences; Patients; Pharmaceutical Preparations; Pharmacogenetics; Pharmacogenomics; Phase; Phenotype; Population; Promoter Regions; Prospective Studies; Proteins; Public Health; Puerto Rican; Race; Reporter; Site; Smooth Muscle Myocytes; Sorting - Cell Movement; System; Testing; Therapeutic; Tissue-Specific Gene Expression; Tobacco Smoke Pollution; Variant; Virus Integration; Work; Zinc Fingers; base; clinical practice; design; exome; experience; genetic variant; genome wide association study; genome-wide; human disease; next generation; nuclease; promoter; public health relevance; racial and ethnic; racial/ethnic difference; rare variant; respiratory smooth muscle; response; success

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.

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处方药物。种族和民族之间对沙丁胺醇的治疗反应存在显着差异。我们证明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哮喘儿科人群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 具有更大的效应量，从而导致沙丁胺醇反应中的种族/民族差异。我们将通过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。总共1500名患有哮喘和极端药物反应表型的少数族裔儿童将被选择进行测序，其中包括波多黎各人（n=500）、墨西哥人（n=500）和非裔美国人（n=500）。通过“Exome-Plus”方法，目标捕获探针组旨在捕获人类外显子 (38 Mb)、>1000 个非编码 RNA 和 6 Mb 定制序列。我们将把“Plus”测序的重点放在确定在气道平滑肌细胞中表达的 2,153 个候选基因中的顺式调控变异以及我们自己的 GWAS 结果上。具体目标 2：识别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) 对高药物反应者和低药物反应者之间的个体变异和汇总变异进行关联测试，并在大型、独立的拉丁裔和非裔美国哮喘受试者组 (n=2,235) 中测试热门命中与 BDR 的关联。然后，我们将在另外 4,980 人身上复制我们的发现。具体目标 3：确定与支气管扩张剂反应相关的启动子变异是否导致初级气道平滑肌细胞中基因表达差异。我们开发了一种基于染色质的启动子报告基因检测，它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。