Linkage analysis of susceptibility to hyperoxia. Nrf2 is a candidate gene

Am J Respir Cell Mol Biol. 2002 Jan;26(1):42-51. doi: 10.1165/ajrcmb.26.1.4536.


A strong role for reactive oxygen species (ROS) has been proposed in the pathogenesis of a number of lung diseases. Hyperoxia (> 95% oxygen) generates ROS and extensive lung damage, and has been used as a model of oxidant injury. However, the precise mechanisms of hyperoxia-induced toxicity have not been completely clarified. This study was designed to identify hyperoxia susceptibility genes in C57BL/6J (susceptible) and C3H/HeJ (resistant) mice. The quantitative phenotypes used for this analysis were pulmonary inflammatory cell influx, epithelial cell sloughing, and hyperpermeability. Genome-wide linkage analyses of intercross (F2) and recombinant inbred cohorts identified significant and suggestive quantitative trait loci on chromosomes 2 (hyperoxia susceptibility locus 1 [Hsl1]) and 3 (Hsl2), respectively. Comparative mapping of Hsl1 identified a strong candidate gene, Nfe2l2 (nuclear factor, erythroid derived 2, like 2 or Nrf2) that encodes a transcription factor NRF2 which regulates antioxidant and phase 2 gene expression. Strain-specific variation in lung Nrf2 messenger RNA expression and a T --> C substitution in the B6 Nrf2 promoter that cosegregated with susceptibility phenotypes in F2 animals supported Nrf2 as a candidate gene. Results from this study have important implications for understanding the mechanisms through which oxidants mediate the pathogenesis of lung disease.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Antioxidants / pharmacology
  • Bronchoalveolar Lavage
  • Chromosome Mapping
  • Crosses, Genetic
  • DNA, Complementary / metabolism
  • DNA-Binding Proteins / genetics*
  • Dose-Response Relationship, Drug
  • Female
  • Genes, Dominant
  • Genetic Linkage*
  • Genetic Predisposition to Disease*
  • Genetic Variation
  • Genome
  • Genotype
  • Hypoxia*
  • Lung / pathology
  • Macrophages / metabolism
  • Male
  • Mice
  • Mice, Inbred C3H
  • Mice, Inbred C57BL
  • Mutation
  • NF-E2-Related Factor 2
  • Oxygen / metabolism
  • Phenotype
  • Polymorphism, Genetic
  • Polymorphism, Restriction Fragment Length
  • Promoter Regions, Genetic
  • RNA, Messenger / metabolism
  • Reactive Oxygen Species*
  • Species Specificity
  • Trans-Activators / genetics*


  • Antioxidants
  • DNA, Complementary
  • DNA-Binding Proteins
  • NF-E2-Related Factor 2
  • Nfe2l2 protein, mouse
  • RNA, Messenger
  • Reactive Oxygen Species
  • Trans-Activators
  • Oxygen