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Am. J. Respir. Cell Mol. Biol., Volume 23, Number 4, October, 2000 537-545

Quantitative Trait Loci Controlling Allergen-Induced Airway Hyperresponsiveness in Inbred Mice

Susan L. Ewart, Douglas Kuperman, Eric Schadt, Clarke Tankersley, Andrew Grupe, Dennis M. Shubitowski, Gary Peltz, and Marsha Wills-Karp

Department of Large Animal Clinical Sciences, Michigan State University, East Lansing, Michigan; Department of Environmental Health Sciences, Johns Hopkins University, Baltimore, Maryland; Department of Biomathematics, University of California, Los Angeles, California; Department of Bioinformatics, Rosette Inpharmatics, Kirkland, Washington; and Roche BioScience, Palo Alto, California

Identification of the genetic loci underlying asthma in humans has been hampered by variability in clinical phenotype, uncontrolled environmental influences, and genetic heterogeneity. To circumvent these complications, the genetic regulation of asthma-associated phenotypes was studied in a murine model. We characterized the strain distribution patterns for the asthma-related phenotypes airway hyperresponsiveness (AHR), lung eosinophils, and ovalbumin (OVA)-specific serum immunoglobulin (Ig) E induced by allergen exposure protocols in A/J, AKR/J, BALB/cJ, C3H/HeJ, and C57BL/6J inbred strains and in (C3H/HeJ × A/J)F1 mice. Expression of AHR differed between strains and was sometimes discordant with lung eosinophils or serum IgE. Furthermore, we identified two distinct quantitative trait loci (QTL) for susceptibility to allergen-induced AHR, Abhr1 (allergen-induced bronchial hyperresponsiveness) (lod = 4.2) and Abhr2 (lod = 3.7), on chromosome 2 in backcross progeny from A/J and C3H/HeJ mice. In addition, a QTL on chromosome 7 was suggestive of linkage to this trait. These QTL differ from those we have previously found to control noninflammatory AHR in the same crosses. Elucidation of the genes underlying these QTL will facilitate the identification of biochemical pathways regulating AHR in animal models of asthma and may provide insights into the pathogenesis of human disease.




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