Am. J. Respir. Cell Mol. Biol., Volume 24, Number 6, June, 2001 740-746

Quantitative Trait Analysis of Nickel-Induced Acute Lung Injury in Mice

Daniel R. Prows and George D. Leikauf

Departments of Environmental Health, Molecular & Cellular Physiology, and Medicine, University of Cincinnati, Cincinnati, Ohio

The genetic determinants underlying susceptibility to acute lung injury have not been identified. Recently, we found that the strain distribution pattern for mean survival time (MST) to three irritantsozone, ultrafine Teflon, and nickel sulfate was shared between inbred mouse strains. For ozone-induced acute lung injury, survival was found to be a complex trait controlled by at least three quantitative trait loci (QTLs), designated Aliq1, Aliq2, and Aliq3. To explore whether similar genes might be involved in survival to acute lung injury induced by nickel sulfate, we took advantage of the 2-fold difference in MSTs between the sensitive A/J and resistant C57BL/6J mice. QTL analysis of 307 backcross mice generated from these strains identified significant linkage to chromosome 6 (proposed as Aliq4) and suggestive linkage on chromosomes 1 and 12. Loci on chromosomes 9 and 16 had lod scores (log of the odds ratio, which equals the log of the "likelihood of linkage divided by the likelihood of no linkage") below significance, but contributed to the overall response. Comparing MSTs of backcross mice with similar haplotypes identified an allelic combination of four QTLs that could account for the survival time difference between the parental strains. Similar QTL intervals on chromosomes 6 and 12 were previously identified with ozone, suggesting that the interplay between different combinations of relatively few genes might be important for irritant-induced acute lung injury survival.

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