A Locus on Chromosome 15 Contributes to Acute Ozone-induced Lung Injury in Collaborative Cross Mice.

Ozone (O 3 )-induced respiratory toxicity varies considerably within the human population and across inbred mouse strains, indicative of gene-environment interactions (GxE). Though previous studies have identified several quantitative trait loci (QTL) and candidate genes underlying responses to O 3 exposure, precise mechanisms of susceptibility remain incompletely described. We sought to update our understanding of the genetic architecture of O 3 responsiveness using the Collaborative Cross (CC) recombinant inbred mouse panel. We evaluated hallmark O 3 -induced inflammation and injury phenotypes in 56 CC strains after exposure to filtered air or 2 ppm O 3 , and performed focused genetic analysis of variation in lung injury, as reflected by protein in lung lavage fluid. Strain-dependent responses to O 3 were clear, and QTL mapping revealed two novel loci on Chr (Chromosomes) 10 (peak, 26.2 Mb; 80% confidence interval [CI], 24.6-43.6 Mb) and 15 (peak, 47.1 Mb; 80% CI, 40.2-54.9 Mb), the latter surpassing the 95% significance threshold. At the Chr 15 locus, C57BL/6J and CAST/EiJ founder haplotypes were associated with higher lung injury responses compared with all other CC founder haplotypes. With further statistical analysis and a weight of evidence approach, we delimited the Chr 15 QTL to an ∼2 Mb region containing 21 genes (10 protein coding) and nominated three candidate genes, namely Oxr1 , Rspo2 , and Angpt1 . Gene and protein expression data further supported Oxr1 and Angpt1 as priority candidate genes. In summary, we have shown that O 3 -induced lung injury is modulated by genetic variation, identified two high priority candidate genes, and demonstrated the value of the CC for detecting GxE.