We first established a mouse model of dust mite-induced asthma that recapitulates the key features of human asthma, namely airway hyper-responsiveness, inflammation, and mucus production. We then applied this model to a newly established population of mice known as the Collaborative Cross (CC). This population captures the more than 95% of the genetic diversity present in all inbred strains of mice. This genetic and resulting phenotypic diversity greatly enhances the power to identify quantitative trait loci (QTL). We phenotyped more than 150 mice and genotyped the mice using a high-density Affymetrix array. Using these data, we identified QTL for airway inflammation, specifically the numbers of macrophages (Chromosome (Chr) 17), eosinophils (Chr 11), and neutrophils (Chr 2) in lung lavage fluid. We also identified a QTL for serum IgG2b.We are currently refining these QTL to identify candidate genes using conditional correlation and additional genome sequence data. We plan to test the role of human homologs of the candidate genes we identify in the mouse in human population-based studies of allergic asthma through collaborations that are already underway with Drs. Cookson and Postma.

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National Human Genome Research Institute
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Donoghue, Lauren J; Livraghi-Butrico, Alessandra; McFadden, Kathryn M et al. (2017) Identification of trans Protein QTL for Secreted Airway Mucins in Mice and a Causal Role for Bpifb1. Genetics 207:801-812
Kelada, Samir N P (2016) Plethysmography Phenotype QTL in Mice Before and After Allergen Sensitization and Challenge. G3 (Bethesda) 6:2857-65
Kelada, Samir N P; Carpenter, Danielle E; Aylor, David L et al. (2014) Integrative genetic analysis of allergic inflammation in the murine lung. Am J Respir Cell Mol Biol 51:436-45
Rutledge, Holly; Aylor, David L; Carpenter, Danielle E et al. (2014) Genetic regulation of Zfp30, CXCL1, and neutrophilic inflammation in murine lung. Genetics 198:735-45
Kelada, Samir N P; Aylor, David L; Peck, Bailey C E et al. (2012) Genetic analysis of hematological parameters in incipient lines of the collaborative cross. G3 (Bethesda) 2:157-65
Kelada, Samir N P; Wilson, Mark S; Tavarez, Urraca et al. (2011) Strain-dependent genomic factors affect allergen-induced airway hyperresponsiveness in mice. Am J Respir Cell Mol Biol 45:817-24
Aylor, David L; Valdar, William; Foulds-Mathes, Wendy et al. (2011) Genetic analysis of complex traits in the emerging Collaborative Cross. Genome Res 21:1213-22