Functional genomic assessment of phosgene-induced acute lung injury in mice. Am J Respir Cell Mol Biol 2013 Sep;49(3):368-83
Date
04/18/2013Pubmed ID
23590305Pubmed Central ID
PMC3824050DOI
10.1165/rcmb.2012-0337OCScopus ID
2-s2.0-84883477803 (requires institutional sign-in at Scopus site) 18 CitationsAbstract
In this study, a genetically diverse panel of 43 mouse strains was exposed to phosgene and genome-wide association mapping performed using a high-density single nucleotide polymorphism (SNP) assembly. Transcriptomic analysis was also used to improve the genetic resolution in the identification of genetic determinants of phosgene-induced acute lung injury (ALI). We prioritized the identified genes based on whether the encoded protein was previously associated with lung injury or contained a nonsynonymous SNP within a functional domain. Candidates were selected that contained a promoter SNP that could alter a putative transcription factor binding site and had variable expression by transcriptomic analyses. The latter two criteria also required that ≥10% of mice carried the minor allele and that this allele could account for ≥10% of the phenotypic difference noted between the strains at the phenotypic extremes. This integrative, functional approach revealed 14 candidate genes that included Atp1a1, Alox5, Galnt11, Hrh1, Mbd4, Phactr2, Plxnd1, Ptprt, Reln, and Zfand4, which had significant SNP associations, and Itga9, Man1a2, Mapk14, and Vwf, which had suggestive SNP associations. Of the genes with significant SNP associations, Atp1a1, Alox5, Plxnd1, Ptprt, and Zfand4 could be associated with ALI in several ways. Using a competitive electrophoretic mobility shift analysis, Atp1a1 promoter (rs215053185) oligonucleotide containing the minor G allele formed a major distinct faster-migrating complex. In addition, a gene with a suggestive SNP association, Itga9, is linked to transforming growth factor β1 signaling, which previously has been associated with the susceptibility to ALI in mice.
Author List
Leikauf GD, Concel VJ, Bein K, Liu P, Berndt A, Martin TM, Ganguly K, Jang AS, Brant KA, Dopico RA Jr, Upadhyay S, Cario C, Di YP, Vuga LJ, Kostem E, Eskin E, You M, Kaminski N, Prows DR, Knoell DL, Fabisiak JPMESH terms used to index this publication - Major topics in bold
Acute Lung InjuryAlleles
Animals
Chemical Warfare Agents
Chromosome Mapping
Electrophoretic Mobility Shift Assay
Female
Gene Expression
Gene Expression Profiling
Genome
Genome-Wide Association Study
Genomics
Genotype
Integrins
Lung
Mice
Mice, Inbred Strains
Oligonucleotide Array Sequence Analysis
Phosgene
Polymorphism, Single Nucleotide
Promoter Regions, Genetic
Sodium-Potassium-Exchanging ATPase
