Asthma affects >300 million people worldwide. Both genetic and environmental factors contribute to risk, but interactions between them are poorly understood. Our studies in COAST children have identified significant gene-environment interactions (GEIs) and at least two independent pathways of risk for human rhinovirus (HRV)-associated wheezing illness in infancy and asthma onset in childhood. One pathway is associated with genotype at the 17q21 asthma locus and a second is associated with allergic sensitization in the first three years of life, expression of FCSRI receptors on peripheral blood dendritic cells, and genotype at the FCERIA locus. Moreover, genotype at the vitamin D receptor (VDR) locus is independently associated with duration and severity of HRV illness in older children. The overall objectives of this proposal are to study global transcriptional (RNA) and epigenetic (methylation) responses to human rhinovirus (HRV) infection in nasal epithelial cells (NECs) from COAST children, and further characterize both 17q21-dependent and 17q21-independent pathways of response. These studies will identify expression quantitative trait loci (eQTLs) and methylation (me)QTLs in HRV-infected and/or in mock-infected NECs, a relevant primary cell model. All functional variants (eQTLs and meQTLs) will be further evaluated for associations with phenotypes assessed in COAST children from birth through adolescence. Lastly, we will build networks of correlated transcriptional responses to characterize the impact of HRV infection on the molecular system in NECs. To our knowledge, these studies will be the first to use a systems genetic approach to elucidate the mechanisms underlying multiple pathways of risk for asthma and to characterize the molecular interactions between genetic and environmental risk factors for asthma in relevant, primary cells. The results of these studies will significantly impact our understanding of asthma pathogenesis, provide a new paradigm for elucidating function in asthma genetics, and potentially identify new pathways for the prevention and treatment of childhood asthma.
Asthma affects >20 million people in the U.S. Wheezing with rhinovirus (RV) infection is a significant risk factor for asthma. We will characterize transcriptional and epigenomic responses to RV in nasal epithelial cells, and build networks of interacting genes to understand the impact of RV on the molecular system. These studies will impact our understanding of asthma pathogenesis and identify new therapeutic pathways.
| Higano, Nara S; Spielberg, David R; Fleck, Robert J et al. (2018) Neonatal Pulmonary Magnetic Resonance Imaging of Bronchopulmonary Dysplasia Predicts Short-Term Clinical Outcomes. Am J Respir Crit Care Med 198:1302-1311 |
| Stein, Michelle M; Thompson, Emma E; Schoettler, Nathan et al. (2018) A decade of research on the 17q12-21 asthma locus: Piecing together the puzzle. J Allergy Clin Immunol 142:749-764.e3 |
| Bønnelykke, Klaus; Coleman, Amaziah T; Evans, Michael D et al. (2018) Cadherin-related Family Member 3 Genetics and Rhinovirus C Respiratory Illnesses. Am J Respir Crit Care Med 197:589-594 |
| Bashir, Hiba; Grindle, Kristine; Vrtis, Rose et al. (2018) Association of rhinovirus species with common cold and asthma symptoms and bacterial pathogens. J Allergy Clin Immunol 141:822-824.e9 |
| Higano, Nara S; Bates, Alister J; Tkach, Jean A et al. (2018) Pre- and post-operative visualization of neonatal esophageal atresia/tracheoesophageal fistula via magnetic resonance imaging. J Pediatr Surg Case Rep 29:5-8 |
| Jackson, Daniel J; Gern, James E; Lemanske Jr, Robert F (2017) Lessons learned from birth cohort studies conducted in diverse environments. J Allergy Clin Immunol 139:379-386 |
| DeVries, Avery; Wlasiuk, Gabriela; Miller, Susan J et al. (2017) Epigenome-wide analysis links SMAD3 methylation at birth to asthma in children of asthmatic mothers. J Allergy Clin Immunol 140:534-542 |
| Higano, Nara S; Hahn, Andrew D; Tkach, Jean A et al. (2017) Retrospective respiratory self-gating and removal of bulk motion in pulmonary UTE MRI of neonates and adults. Magn Reson Med 77:1284-1295 |
| Barkal, Layla J; Procknow, Clare L; Álvarez-García, Yasmín R et al. (2017) Microbial volatile communication in human organotypic lung models. Nat Commun 8:1770 |
| Higano, Nara S; Fleck, Robert J; Spielberg, David R et al. (2017) Quantification of neonatal lung parenchymal density via ultrashort echo time MRI with comparison to CT. J Magn Reson Imaging 46:992-1000 |
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