Genetic interactions between chromosomes 11 and 18 contribute to airway hyperresponsiveness in mice

• Published in: PloS one Vol. 7; no. 1; p. e29579
• Main Authors: Ferreira, Caroline M, Chen, James L, Li, Jianrong, Shimomura, Kazuhiro, Yang, Xinan, Lussier, Yves A, Pinto, Lawrence H, Solway, Julian
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 10.01.2012; Public Library of Science (PLoS)
• Subjects: Animals; Apolipoproteins; Asthma; Atherosclerosis; Bioinformatics; Biology; Bronchial Hyperreactivity - genetics; Cholesterol; chromosome 11; Chromosomes; Chromosomes, Mammalian - genetics; Crosses, Genetic; Data processing; Drug dosages; Female; Gene mapping; Genes; Genetic analysis; Genetic aspects; Genetic Predisposition to Disease; Genotypes; House mouse; Inflammation; Influence; Intravenous administration; Laboratory animals; Lod Score; Male; Medicine; Methacholine; Mice; Mice, Inbred C57BL; Network analysis; Neurobiology; Neurosciences; Npc1 protein; Ostomy; Phenotypes; Physiology; Polymorphism, Single Nucleotide - genetics; Protein Interaction Maps - genetics; Proteins; Quantitative genetics; Quantitative trait loci; Quantitative Trait Loci - genetics; Respiratory tract; Rodents; Single-nucleotide polymorphism; Smooth muscle; Studies; Two dimensional analysis; United States > US; Illinois; Chicago Illinois
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0029579

We used two-dimensional quantitative trait locus analysis to identify interacting genetic loci that contribute to the native airway constrictor hyperresponsiveness to methacholine that characterizes A/J mice, relative to C57BL/6J mice. We quantified airway responsiveness to intravenous methacholine boluses in eighty-eight (C57BL/6J X A/J) F₂ and twenty-seven (A/J X C57BL/6J) F₂ mice as well as ten A/J mice and six C57BL/6J mice; all studies were performed in male mice. Mice were genotyped at 384 SNP markers, and from these data two-QTL analyses disclosed one pair of interacting loci on chromosomes 11 and 18; the homozygous A/J genotype at each locus constituted the genetic interaction linked to the hyperresponsive A/J phenotype. Bioinformatic network analysis of potential interactions among proteins encoded by genes in the linked regions disclosed two high priority subnetworks--Myl7, Rock1, Limk2; and Npc1, Npc1l1. Evidence in the literature supports the possibility that either or both networks could contribute to the regulation of airway constrictor responsiveness. Together, these results should stimulate evaluation of the genetic contribution of these networks in the regulation of airway responsiveness in humans.