Asthma is a chronic respiratory disease that affects over 300 million individuals worldwide and 20 million Americans. Corticosteroids (CS) are the most potent, anti-inflammatory drugs used for the control of asthma. However, substantial inter-individual variability in drug response has been reported, whereas the intra- individual response was highly repeatable, suggesting a genetic component. Previous pharmacogenetic studies of CS response focused primarily on common genetic polymorphisms, with poor representation of rare variants (minor allele frequency <0.05), which likely explain part of the missing heritabilit. We hypothesize that novel coding variants, identified through next-generation sequencing of whole exomes, modulate CS response in asthma. This proposal outlines a translational genomics approach for identifying functional variants associated with CS response in asthma patients. First, we will identify all coding (non-synonymous and splice) variants from the exomes of 200 asthma patients. Then, we will perform a comprehensive analysis of CS response whereby we test each common variant individually but group all rare variants within a gene together to determine their collective effect. Then, we propose to test the function of up to three associated coding variants using in vitro experiments in cellular models. These findings will improve our understanding of CS response variability in asthma, with potentially wider implications as this class of medications is used to treat other immune diseases such as rheumatoid arthritis and adrenal disorders. This investigation will serve as an important step in personalized medicine by identifying novel genomic loci influencing CS response with the ultimate goal of facilitating the development of genomic-based prognostic tests.
/PUBLIC HEALTH RELEVANCE STATEMENT Asthma is a one of the most common chronic diseases in children and adults. Despite the availability of several classes of asthma treatments including corticosteroids to control airway inflammation, there is substantial inter- individual variability in drug response. The ability to determine who would benefit from existing asthma medications would improve patient care by reducing morbidity and mortality as well as health care costs. This K99/R00 grant proposes to identify novel genetic factors that contribute to the variability in response to corticosteroids. A better understanding of the genetic components underlying drug response phenotype will improve patient care and reduce the asthma burden.