title: Interacting genetic loci cause airway hyperresponsiveness.
abstract: 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 backcrossing 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. Quantitative trait linkage (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 have important implications for the dissection of the genetic etiology of asthma in humans.
authors.affiliation: Division of Genetics, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Kate G
authors.initials: KG
authors.lastname: Ackerman
authors.forename: Hailu
authors.initials: H
authors.lastname: Huang
authors.forename: Hartmut
authors.initials: H
authors.lastname: Grasemann
authors.forename: Chris
authors.initials: C
authors.lastname: Puma
authors.forename: Jonathan B
authors.initials: JB
authors.lastname: Singer
authors.forename: Annie E
authors.initials: AE
authors.lastname: Hill
authors.forename: Eric
authors.initials: E
authors.lastname: Lander
authors.forename: Joseph H
authors.initials: JH
authors.lastname: Nadeau
authors.forename: Gary A
authors.initials: GA
authors.lastname: Churchill
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Drazen
authors.forename: David R
authors.initials: DR
authors.lastname: Beier
mesh_terms: D000818:Animals; D001249:Asthma / Q000235:genetics*; D016535:Bronchial Hyperreactivity / Q000235:genetics*; D002874:Chromosome Mapping; D003433:Crosses, Genetic; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D016678:Genome; D005838:Genotype; D051379:Mice; D020297:Mice, Congenic; D008810:Mice, Inbred C57BL; D015233:Models, Statistical; D010375:Pedigree; D010641:Phenotype; D040641:Quantitative Trait Loci; D019655:Quantitative Trait, Heritable