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1 Division of Genetics, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA; Division of Emergency Medicine, Children's Hospital, Boston, MA, USA
2 Division of Genetics, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
3 Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
4 Broad Institute, Cambridge, MA, USA
5 Genetics, Case Western Reserve University, Cleveland, OH, USA
6 The Jackson Laboratory, Bar Harbor, ME, USA
* To whom correspondence should be addressed. E-mail: beier{at}receptor.med.harvard.edu.
Airway hyperresponsiveness (AHR)is a key physiological component of asthma, and the genetic basis of this complex trait has remained elusive. We created recombinant congenic mice with increased naive AHR by serially back-crossing A/J mice (which have elevated naive AHR) with C57BL/6J mice, and selecting for mice with an elevated naive AHR phenotype. The seventh backcross-generation hyperresponsive mice retained A/J loci in three regions. QTL analysis of 123 unselected N8 progeny demonstrated that the AHR phenotype was not associated with any single locus, but was significantly associated with an interaction of loci on chromosomes 2 and 6. These findings were confirmed in an independent analysis of chromosome substitution strain mice. The identification of genomic regions containing loci causally associated with AHR, and the demonstration that this trait requires their interaction, has important implications for the dissection of the genetic etiology of asthma in humans.
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