Based on currently available data, we believe that airway responsiveness is an independent, quantitative trait of the asthmatic lesion that is under genetic control. It is known that the variability in airway responsiveness within a given strain of inbred mice is small while the variability in airway responsiveness among strains is quite substantial. The presence of strain-related phenotypic variability in airway responsiveness in mice suggests the possibility that the genetic loci specifically responsible for airway responsiveness can be identified through appropriate genetic studies. The availability of extended chromosome maps for the mouse, computer programs for tracking multiple genetic loci which contribute in an quantitative way to a given phenotypic trait, and the ability to perform molecular genetic mapping with high resolution on small quantities of blood, now make it possible to define genetic linkage for quantitative traits. Airway responsiveness to methacholine as well as 5-hydroxytryptamine (5- HT) as indicated by the infused dose required to decrease pulmonary conductance (GL) by 50% will be determined in A/J, C57BL/6, C57BL/6xA/J F1 and recombinant inbred (RI) mice derived from these progenitor strains. The responsiveness data will be subject to analysis to determine if one or more than one genetic locus influences airway responsiveness to each mediator and whether there exists common loci that influence airway responsiveness to both mediators. Once the mode of inheritance and its mono- or polygenic nature is established mice derived from appropriate crosses will be genotyped using polymorphic markers that span the genome at 10 cM intervals. The data will be subject to linkage analysis using a strategy that allows consideration of either single or multiple genes to influence the phenotypical expression of airway responsiveness as a quantitative trait. In particular, linkage will be sought between the inheritance pattern of polymorphic markers and the airway responsiveness phenotype. Candidate loci, identified through primary analysis will be mapped at 2.0 cM intervals.
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