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Reciprocal Congenic Lines of Mice Capture the Aliq1 Effect on Acute Lung Injury Survival Time

¹ Division of Human Genetics, Children's Hospital Medical Center, Cincinnati, Ohio; ² Department of Pediatrics, ³ Department of Environmental Health, Center for Environmental Genetics, and ⁷ Department of Pulmonary and Critical Care Medicine, University of Cincinnati, Cincinnati, Ohio; ⁴ Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology, Cambridge, Massachusetts; ⁵ Genetics Department, Case Western Reserve University School of Medicine, Cleveland, Ohio; and ⁶ Center for Human Genetics, University Hospitals of Cleveland, Cleveland, Ohio

Correspondence and requests for reprints should be addressed to Daniel R. Prows at: Children's Hospital Medical Center, Division & Program in Human Genetics, 3333 Burnet Ave., MLC 7016, Building R, Room 1464, Cincinnati, OH 45229-3039. E-mail: daniel.prows{at}cchmc.org

Acute lung injury (ALI) is a devastating condition resulting from diverse causes. Genetic studies of human populations indicate that ALI is a complex disease with substantial phenotypic variance, incomplete penetrance, and gene–environment interactions. To identify genes controlling ALI mortality, we previously investigated mean survival time (MST) differences between sensitive A/J (A) and resistant C57BL/6J (B) mice in ozone using quantitative trait locus (QTL) analysis. MST was significantly linked to QTLs (Aliq1-3) on chromosomes 11, 13, and 17, respectively. Additional QTL analyses of separate and combined backcross and F₂ populations supported linkage to Aliq1 and Aliq2, and established significance for previously suggestive QTLs on chromosomes 7 and 12 (named Aliq5 and Aliq6, respectively). Decreased MSTs of corresponding chromosome substitution strains (CSSs) verified the contribution of most QTL-containing chromosomes to ALI survival. Multilocus models demonstrated that three QTLs could explain the MST difference between progenitor strains, agreeing with calculated estimates for number of genes involved. Based on results of QTL genotype analysis, a double CSS (B.A-6,11) was generated that contained Aliq1 and Aliq4 chromosomes. Surprisingly, MST and pulmonary edema after exposure of B.A-6,11 mice were comparable to B mice, revealing an unpredicted loss of sensitivity compared with separate CSSs. Reciprocal congenic lines for Aliq1 captured the corresponding phenotype in both background strains and further refined the QTL interval. Together, these findings support most of the previously identified QTLs linked to ALI survival and established lines of mice to further resolve Aliq1.

Key Words: acute respiratory distress syndrome • chromosome substitution strain • congenic • mean survival • pulmonary edema

CLINICAL RELEVANCE This work verifies previous regions linked to acute lung injury (ALI) survival. Results have refined the Chr 11 region that contains Aliq1, a significant susceptibility locus for ALI survival, and has established separate lines of congenic mice to further resolve Aliq1.