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.
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 patients and racial/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 children with asthma; which may lead to more targeted therapies. Results from this proposal will inform public health policy and clinical practice.
|Neophytou, Andreas M; Oh, Sam S; White, Marquitta J et al. (2018) Secondhand smoke exposure and asthma outcomes among African-American and Latino children with asthma. Thorax 73:1041-1048|
|Spear, Melissa L; Hu, Donglei; Pino-Yanes, Maria et al. (2018) A genome-wide association and admixture mapping study of bronchodilator drug response in African Americans with asthma. Pharmacogenomics J :|
|Zeiger, Andrew M; White, Marquitta J; Eng, Celeste et al. (2018) Genetic Determinants of Telomere Length in African American Youth. Sci Rep 8:13265|
|Mangul, Serghei; Yang, Harry Taegyun; Strauli, Nicolas et al. (2018) ROP: dumpster diving in RNA-sequencing to find the source of 1 trillion reads across diverse adult human tissues. Genome Biol 19:36|
|Levin, Albert M; Gui, Hongsheng; Hernandez-Pacheco, Natalia et al. (2018) Integrative approach identifies corticosteroid response variant in diverse populations with asthma. J Allergy Clin Immunol :|
|Sun, Xiaobo; Gao, Jingjing; Jin, Peng et al. (2018) Optimized distributed systems achieve significant performance improvement on sorted merging of massive VCF files. Gigascience 7:|
|Mak, Angel C Y; White, Marquitta J; Eckalbar, Walter L et al. (2018) Whole-Genome Sequencing of Pharmacogenetic Drug Response in Racially Diverse Children with Asthma. Am J Respir Crit Care Med 197:1552-1564|
|Park, Danny S; Eskin, Itamar; Kang, Eun Yong et al. (2018) An ancestry-based approach for detecting interactions. Genet Epidemiol 42:49-63|
|Gour, Naina; Lajoie, Stephane; Smole, Ursula et al. (2018) Dysregulated invertebrate tropomyosin-dectin-1 interaction confers susceptibility to allergic diseases. Sci Immunol 3:|
|Zaitlen, Noah; Huntsman, Scott; Hu, Donglei et al. (2017) The Effects of Migration and Assortative Mating on Admixture Linkage Disequilibrium. Genetics 205:375-383|
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