Airway hyperresponsiveness to acetylcholine: segregation analysis and evidence for linkage to murine chromosome 6.
A genetic predisposition to nonspecific airway hyperresponsiveness (AHR) can be demonstrated in humans and in many animal models. The goal of the current study was to gain insight into the molecular mechanisms that determine AHR by mapping the genes that control this phenotype. We describe genetic studies in a mouse model of differential sensitivity to acetylcholine (ACh)-induced AHR. This model was used to ascertain the number, magnitude of effect, and chromosomal location of quantitative trait loci (QTL) providing susceptibility to ACh-induced AHR. Segregation analyses indicated that a major locus acting additively with a polygenic effect segregates with the airway pressure-time index (APTI) in the progeny of hyperresponsive A/J and hyporesponsive C3H/HeJ mice. Additionally, four loci segregate with respiratory system resistance (Rrs). Examination of the genome for markers linked to these phenotypes indicated that a QTL on chromosome 6 was common to both traits. QTL analysis in the [(C3H/HeJ x A/J)F1 x A/J] backcross generation revealed significant linkage for ACh-induced AHR within the interval spanning the chromosome 6 deoxyribonucleic acid (DNA) markers D6Mit16 and D6Mit13. A/J alleles in this interval were associated with significantly greater airway responsiveness than were C3H/HeJ alleles. Several important candidate genes map to this region, including the locus for the interleukin-5 (IL-5) receptor. This mapping information in the mouse may relate to human studies in which bronchial hyperresponsiveness links to the chromosomal region containing the gene for IL-5 (1).
Ewart
S L
SL
Department of Anesthesiology, Johns Hopkins Medical Institutions, Baltimore, Maryland, USA.
Mitzner
W
W
DiSilvestre
D A
DA
Meyers
D A
DA
Levitt
R C
RC
D000109:Acetylcholine / Q000494:pharmacology*; D000818:Animals; D016535:Bronchial Hyperreactivity / Q000139:chemically induced / Q000235:genetics*; D002874:Chromosome Mapping; D003433:Crosses, Genetic; D004276:DNA, Satellite / Q000737:chemistry; D005260:Female; D008040:Genetic Linkage; D005819:Genetic Markers; D016678:Genome; D005838:Genotype; D006801:Humans; D008297:Male; D051379:Mice; D008805:Mice, Inbred A / Q000235:genetics*; D008809:Mice, Inbred C3H / Q000235:genetics*; D008957:Models, Genetic; D010641:Phenotype
D004276:DNA, Satellite; D005819:Genetic Markers; D000109:Acetylcholine