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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL070831-12
Application #
8743243
Study Section
Heart, Lung, and Blood Program Project Review Committee (HLBP)
Project Start
Project End
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
12
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Wisconsin Madison
Department
Type
DUNS #
City
Madison
State
WI
Country
United States
Zip Code
53715
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
B√łnnelykke, 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
Ober, Carole; Sperling, Anne I; von Mutius, Erika et al. (2017) Immune development and environment: lessons from Amish and Hutterite children. Curr Opin Immunol 48:51-60
Hahn, Andrew D; Higano, Nara S; Walkup, Laura L et al. (2017) Pulmonary MRI of neonates in the intensive care unit using 3D ultrashort echo time and a small footprint MRI system. J Magn Reson Imaging 45:463-471
Rubner, Frederick J; Jackson, Daniel J; Evans, Michael D et al. (2017) Early life rhinovirus wheezing, allergic sensitization, and asthma risk at adolescence. J Allergy Clin Immunol 139:501-507
Turunen, Riitta; Vuorinen, Tytti; Bochkov, Yury et al. (2017) Clinical and Virus Surveillance After the First Wheezing Episode: Special Reference to Rhinovirus A and C Species. Pediatr Infect Dis J 36:539-544
Liu, Y-P; Rajamanikham, V; Baron, M et al. (2017) Association of ORMDL3 with rhinovirus-induced endoplasmic reticulum stress and type I Interferon responses in human leucocytes. Clin Exp Allergy 47:371-382

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