AIRWAY HYPERRESPONSIVENESS TO ACETYLCHOLINE - SEGREGATION ANALYSIS AND EVIDENCE FOR LINKAGE TO MURINE CHROMOSOME-6

A genetic predisposition to nonspecific airway hyperresponsiveness (AH R) can be demonstrated in humans and in many animal models, The goal o f the current study was to gain insight into the molecular mechanisms that determine AHR by mapping the genes that control this phenotype. W e describe genetic studies in a mouse model of differential sensitivit y to acetylcholine (ACh)-induced AHR, This model was used to ascertain the number, magnitude of effect, and chromosomal location of quantita tive trait loci (QTL) providing susceptibility to ACh-induced AHR, Seg regation analyses indicated that a major locus acting additively with a polygenic effect segregates with the airway pressure-time index (APT I) in the progeny of hyperresponsive A/J and hyporesponsive C3H/HeJ mi ce. Additionally, four loci segregate with respiratory system resistan ce (R(s)). Examination of the genome for markers linked to these pheno types indicated that a QTL on chromosome 6 was common to both traits. QTL analysis in the [(C3H/HeJ x A/J)F-1 x A/J] backcross generation re vealed significant linkage for ACh-induced AHR within the interval spa nning the chromosome 6 deoxyribonucleic acid (DNA) markers D6Mit16 and D6Mit13. A/J alleles in this interval were associated with significan tly greater airway responsiveness than were C3H/HeJ alleles. Several i mportant candidate genes map to this region, including the locus for t he interleukin-5 (IL-5) receptor. This mapping information in the mous e may relate to human studies in which bronchial hyperresponsiveness l inks to the chromosomal region containing the gene for IL-5 (1).