Pharmacogenomics of Bronchodilator Response in Minority Children with Asthma

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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.