title: Association of Nrf2 polymorphism haplotypes with acute lung injury phenotypes in inbred strains of mice.
abstract: OBJECTIVE
  Nrf2 is a master transcription factor for antioxidant response element (ARE)-mediated cytoprotective gene induction. A protective role for pulmonary Nrf2 was determined in model oxidative disorders, including hyperoxia-induced acute lung injury (ALI). To obtain additional insights into the function and genetic regulation of Nrf2, we assessed functional single nucleotide polymorphisms (SNPs) of Nrf2 in inbred mouse strains and tested whether sequence variation is associated with hyperoxia susceptibility.
  
  
  RESULTS
  Nrf2 SNPs were compiled from publicly available databases and by re-sequencing DNA from inbred strains. Hierarchical clustering of Nrf2 SNPs categorized the strains into three major haplotypes. Hyperoxia susceptibility was greater in haplotypes 2 and 3 strains than in haplotype 1 strains. A promoter SNP -103 T/C adding an Sp1 binding site in haplotype 2 diminished promoter activation basally and under hyperoxia. Haplotype 3 mice bearing nonsynonymous coding SNPs located in (1862 A/T, His543Gln) and adjacent to (1417 T/C, Thr395Ile) the Neh1 domain showed suppressed nuclear transactivation of pulmonary Nrf2 relative to other strains, and overexpression of haplotype 3 Nrf2 showed lower ARE responsiveness than overexpression of haplotype 1 Nrf2 in airway cells. Importantly, we found a significant correlation of Nrf2 haplotypes and hyperoxic lung injury phenotypes.
  
  
  CONCLUSIONS
  The results indicate significant influence of Nrf2 polymorphisms and haplotypes on gene function and hyperoxia susceptibility. Our findings further support Nrf2 as a genetic determinant in ALI pathogenesis and provide useful tools for investigators who use mouse strains classified by Nrf2 haplotypes to elucidate the role for Nrf2 in oxidative disorders.
authors.affiliation: 1 Laboratory of Respiratory Biology, National Institute of Environmental Health Sciences, National Institutes of Health , Research Triangle Park, North Carolina.
authors.forename: Hye-Youn
authors.initials: HY
authors.lastname: Cho
authors.forename: Anne E
authors.initials: AE
authors.lastname: Jedlicka
authors.forename: Wesley
authors.initials: W
authors.lastname: Gladwell
authors.forename: Jacqui
authors.initials: J
authors.lastname: Marzec
authors.forename: Zackary R
authors.initials: ZR
authors.lastname: McCaw
authors.forename: Rachelle J
authors.initials: RJ
authors.lastname: Bienstock
authors.forename: Steven R
authors.initials: SR
authors.lastname: Kleeberger
mesh_terms: D055371:Acute Lung Injury / Q000235:genetics*; D000818:Animals; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D018496:Hyperoxia / Q000235:genetics; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008958:Models, Molecular; D051267:NF-E2-Related Factor 2 / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D017433:Protein Structure, Secondary; D017422:Sequence Analysis, DNA
chemical_list: D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse