Asthma affects an estimated 300 million individuals worldwide and is the leading cause of childhood hospitalizations in the United States. Leukotriene modifiers are the only common orally-administered class of asthma medications and, thus, are generally preferred among patients. However, the treatment response to leukotriene modifiers is highly heterogeneous, with as many as one-half of all patients being non-responders. Pharmacogenetics provides the promise of "personalized medicine", whereby an individual's response to therapy will be guided by his or her genetic make-up. However, the translation of this promise to the clinical realm has been slow. Recent advances in genomic technologies including expression microarrays and highthroughput genotyping platforms offer an unprecedented opportunity to advance this process;combining expression data with genotype data has been shown to be a powerful methodologic approach. The major goal of this project is to demonstrate that identifying genetic variants contributing to the expression response to leukotriene modifiers can lead to rapid discovery of genetic markers associated with the clinical response with these medications in asthma. We have structured our specific aims to accomplish this goal as follows: 1. Genotyping has been completed on over 550,000 single nucleotide polymorphisms (SNPs) in 400 parent-child trios participating in a longitudinal asthma cohort. Microarray expression experiments will be performed with and without treatment with the leukotriene modifier, zileuton, in immortalized B-lymphocyte cell lines derived from each of the 400 asthmatic probands (the "child" from the parent-child trios). 2. Genome-wide association studies will be conducted using expression differences in response to zileuton as the primary outcome variable. Expression quantitative trait loci (eQTL), those SNPs with the greatest association with pharmacologically induced expression differences, will be identified. 3. The most salient of eQTLs identified using asthmatic cells will be tested for clinical validation using DNA and information from a previously completed clinical trial of asthmatics taking zileuton. 4. The eQTLs associated with zileuton response will also be tested for further validation using asthmatic subjects taking a second type of leukotriene modifier, montelukast, in two additional completed clinical trials. These findings may ultimately lead to the formation of a prognostic test for response to leukotriene modifiers in asthma. Additionally, by integrating genomic expression with population genetics, this approach may be generalizable to the rapid identification of other pharmacogenetic or gene by environment loci. Thesaurus Terms: Asthma, leukotriene, pharmacogenetics, gene expression, microarray, genomics, pharmacogenomics, genome-wide association study, clinical research.
This project seeks to identify genetic markers most closely associated with the genetic expression signature resulting from administration of medications that block the leukotriene pathway in asthma. By demonstrating that these markers also correlate with the clinical response in asthma, the markers may eventually be used to help predict therapeutic response to anti-leukotriene medications in asthma. Since asthma remains the leading cause of childhood hospitalizations and school absences in the United States, optimizing pharmacologic therapy has the potential to substantially decrease the morbidity and financial burden related to this disease.
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