Rhinovirus-triggered acute asthma exacerbation is a dominant cause of morbidity among children with asthma. There is marked inter-individual variation in the susceptibility to and severity of rhinovirus-triggered asthma exacerbation, ranging from mild symptoms to life-threatening episodes. Genetic background likely plays a key role in regulating the clinical phenotype of rhinovirus infection, but the genetic variants that contribute to inter- individual differences in the frequency and severity of rhinovirus-triggered exacerbation are poorly understood. This proposal details a four-year project to provide Dr. David Kantor with the training and expertise in quantitative genomic methods to systematically identify host genetic variants that contribute to inter-individual differences in the clinical phenotype of rhinovirus infection. This approach involves: 1) identifying genetic variants associated with allergic sensitization, 2) identifying novel gene expression patterns associated with the susceptibility to and severity of rhinovirus-triggered asthma exacerbation, 3) mapping condition-specific genetic variants that regulate the gene expression response to rhinovirus, focusing on genes that are associated with the susceptibility to and severity of rhinovirus-triggered asthma exacerbation, and 4) identifying candidate genetic variants that are associated with the susceptibility to rhinovirus-triggered asthma exacerbation. Investigating the basis of variation in the clinical phenotype of rhinovirus infection represents an opportunity to identify the biological mechanisms that pre-dispose some children to severe episodes of rhinovirus-triggered asthma exacerbation. The overall innovation of this approach is that it will allow the identification of condition- specific genes and regulatory genetic variants that are associated with the susceptibility to and severity of rhinovirus-triggered asthma exacerbation. The candidate genes and regulatory genetic variants identified here will be prioritized for functional and validation studies, which ultimately will help drive therapeutic advances. Dr. Kantor will be mentored by Dr. Joel Hirschhorn, a leading authority in genetic association methods, as well as an extraordinary team of researchers, including Drs. Wanda Phipatanakul, Benjamin Raby, and Bruce Levy, who have committed their time, resources, and expertise to facilitate Dr. Kantor's career development. During this award period, Dr. Kantor will develop expertise in clinical research methods to study environmental exposures and statistical methods to analyze genome-scale data. The mentorship team and the institutional environment are an ideal combination to promote career development and collaboration related to studying how gene environment interactions influence disease susceptibility and severity in children. Dr. Kantor has a solid foundation in molecular biology, having earned a PhD in Neuroscience from Johns Hopkins University School of Medicine. Dr. Kantor will emerge from this K23 as an expert in gene-environment interactions, who can apply quantitative statistical methods to identify promising genetic associations, and then utilize his molecular biology training to drill down on those associations to discover causal biological mechanisms.
Rhinovirus triggered asthma exacerbation is a dominant cause of morbidity among children with asthma, and is associated with considerable individual and societal costs. There is marked inter-individual variation in the susceptibility to and severity of rhinovirus-triggered asthma exacerbation, ranging from mild symptoms to life- threatening episodes. Genetic background likely plays a key role in regulating the clinical phenotype of rhinovirus infection, but the genetic variants that contribute to inter-individual differences in the frequency and severity of rhinovirus-triggered exacerbation are poorly understood. The goal of this project is to identify candidate genes and regulatory genetic variants that contribute to inter-individual differences in disease manifestation following rhinovirus infection. Characterizing the genetic basis of inter-individual variation in response to rhinovirus infection is a key step in dissecting the causal biological mechanisms that underlie disease susceptibility and severity, and will ultimately drive therapeutic advances.
| Kantor, David B; Phipatanakul, Wanda; Hirschhorn, Joel N (2018) Gene-Environment Interactions Associated with the Severity of Acute Asthma Exacerbation in Children. Am J Respir Crit Care Med 197:545-547 |
| Kantor, David B; Hirshberg, Eliotte L; McDonald, Molly C et al. (2018) Fluid Balance Is Associated with Clinical Outcomes and Extravascular Lung Water in Children with Acute Asthma Exacerbation. Am J Respir Crit Care Med 197:1128-1135 |
| Kantor, David B; Petty, Carter R; Phipatanakul, Wanda et al. (2018) Transcutaneous CO-oximetry differentiates asthma exacerbation and convalescence in children. J Allergy Clin Immunol 142:676-678.e5 |
