title: Functional genomic assessment of phosgene-induced acute lung injury in mice.
abstract: 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.
authors.affiliation: Department of Environmental and Occupational Health, Graduate School of Public Health, University of Pittsburgh, PA 15219, USA. gleikauf@pitt.edu
authors.forename: George D
authors.initials: GD
authors.lastname: Leikauf
authors.forename: Vincent J
authors.initials: VJ
authors.lastname: Concel
authors.forename: Kiflai
authors.initials: K
authors.lastname: Bein
authors.forename: Pengyuan
authors.initials: P
authors.lastname: Liu
authors.forename: Annerose
authors.initials: A
authors.lastname: Berndt
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Martin
authors.forename: Koustav
authors.initials: K
authors.lastname: Ganguly
authors.forename: An Soo
authors.initials: AS
authors.lastname: Jang
authors.forename: Kelly A
authors.initials: KA
authors.lastname: Brant
authors.forename: Richard A
authors.initials: RA
authors.lastname: Dopico
authors.forename: Swapna
authors.initials: S
authors.lastname: Upadhyay
authors.forename: Clinton
authors.initials: C
authors.lastname: Cario
authors.forename: Y P Peter
authors.initials: YP
authors.lastname: Di
authors.forename: Louis J
authors.initials: LJ
authors.lastname: Vuga
authors.forename: Emrah
authors.initials: E
authors.lastname: Kostem
authors.forename: Eleazar
authors.initials: E
authors.lastname: Eskin
authors.forename: Ming
authors.initials: M
authors.lastname: You
authors.forename: Naftali
authors.initials: N
authors.lastname: Kaminski
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Prows
authors.forename: Daren L
authors.initials: DL
authors.lastname: Knoell
authors.forename: James P
authors.initials: JP
authors.lastname: Fabisiak
mesh_terms: D055371:Acute Lung Injury / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000483:Alleles; D000818:Animals; D002619:Chemical Warfare Agents / Q000633:toxicity*; D002874:Chromosome Mapping; D024202:Electrophoretic Mobility Shift Assay; D005260:Female; D015870:Gene Expression / Q000187:drug effects*; D020869:Gene Expression Profiling; D016678:Genome; D055106:Genome-Wide Association Study; D023281:Genomics; D005838:Genotype; D016023:Integrins / Q000235:genetics / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008815:Mice, Inbred Strains; D020411:Oligonucleotide Array Sequence Analysis; D010705:Phosgene / Q000633:toxicity*; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D000091042:Reelin Protein; D000254:Sodium-Potassium-Exchanging ATPase / Q000235:genetics / Q000378:metabolism
chemical_list: D002619:Chemical Warfare Agents; D016023:Integrins; D000091042:Reelin Protein; D010705:Phosgene; C000717128:Reln protein, mouse; C497344:Atp1a1 protein, mouse; D000254:Sodium-Potassium-Exchanging ATPase