Gene-environment interactions in asthma in mice and humans

National Human Genome Research Institute

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Abstract

We have 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. In order to identify genes that mediate susceptibility to these two phenotypes, we are conducting a large quantitative trait locus (QTL) mapping project using a newly establishing population of genetically diverse mice known as the Collaborative Cross (CC). Mice from the CC are derived from an eight-way cross of common (A/J, C57BL/6J, 129/SvImJ, NOD/ShILtJ and NZO/HILtJ) and wild-derived (WSB/EiJ, PWK/PhJ and CAST/EiJ) inbred strains. The CC was designed to capture maximal genetic diversity of inbred strains and at the same time minimize the effects of population structure, thereby overcoming many of the limitations of previous mapping approaches. Thus far, we have phenotyped more than 150 mice and have made three notable observations: (1) these mice exhibit an incredible range of asthma phenotype diversity, (2) baseline lung function is strongly correlated with lung function after Der p 1 challenge, and (3) the degree of airway inflammation caused by Derp1 does not correlate with impaired lung function. We are now mapping the QTLs in collaboration with colleagues at the University of North Carolina and the Jackson Laboratory. Once QTL have been identified, we plan to test the role of human homologs in population-based studies of allergic asthma through collaborations that are already underway.