Functional polymorphisms in the transcription factor NRF2 in humans increase the risk of acute lung injury

Jacqui M. Marzec, Jason D. Christie, Sekhar P. Reddy, Anne E. Jedlicka, Hue Vuong, Paul N. Lanken, Richard Aplenc, Tae Yamamoto, Masayuki Yamamoto, Hye Youn Cho, Steven R. Kleeberger

Research output: Contribution to journalArticle

250 Citations (Scopus)

Abstract

We recently used positional cloning to identify the transcription factor Nrf2 (NF-E2 related factor 2) as a susceptibility gene in a murine model of oxidant-induced acute lung injury (ALI). NRF2 binds to antioxidant response elements (ARE) and up-regulates protective detoxifying enzymes in response to oxidative stress. This led us to investigate NRF2 as a candidate susceptibility gene for risk of development of ALI in humans. We identified multiple single nucleotide polymorphisms (SNPs) by resequencing NRF2 in ethnically diverse subjects, and one (-617 C/A) significantly (P<0.001) diminished luciferase activity of promoter constructs containing the SNP and significantly decreased the binding affinity (P<0.001) relative to the wild type at this locus (-617 CC). In a nested case-control study, patients with the -617 A SNP had a significantly higher risk for developing ALI after major trauma (OR 6.44; 95% CI 1.34, 30.8; P=0.021) relative to patients with the wild type (-617 CC). This translational investigation provides novel insight into the molecular mechanisms of susceptibility to ALI and may help to identify patients who are predisposed to develop ALI under at risk conditions, such as trauma and sepsis. Furthermore, these findings may have important implications in other oxidative stress related illnesses.

Original languageEnglish
Pages (from-to)2237-2246
Number of pages10
JournalFASEB Journal
Volume21
Issue number9
DOIs
Publication statusPublished - 2007 Jul 1
Externally publishedYes

Keywords

  • ALI
  • Acute respiratory distress syndrome
  • Antioxidant
  • Oxidative stress
  • Reactive oxygen species
  • Translational
  • Trauma

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

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  • Cite this

    Marzec, J. M., Christie, J. D., Reddy, S. P., Jedlicka, A. E., Vuong, H., Lanken, P. N., Aplenc, R., Yamamoto, T., Yamamoto, M., Cho, H. Y., & Kleeberger, S. R. (2007). Functional polymorphisms in the transcription factor NRF2 in humans increase the risk of acute lung injury. FASEB Journal, 21(9), 2237-2246. https://doi.org/10.1096/fj.06-7759com