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

Jacqui M. Marzec^*,1, Jason D. Christie^,,1, Sekhar P. Reddy, Anne E. Jedlicka, Hue Vuong, Paul N. Lanken, Richard Aplenc^||, Tae Yamamoto^¶, Masayuki Yamamoto^¶, Hye-Youn Cho^* and Steven R. Kleeberger^*,2

^* Laboratory of Respiratory Biology, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina, USA;

Center for Clinical Epidemiology Biostatistics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA;

Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA;

Pulmonary, Allergy and Critical Care Division, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA;

^|| Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA; and

^¶ Center for TARA, University of Tsukuba, Tennoudai, Tsukuba, Japan

²Correspondence: National Institute of Environmental Health Sciences, 111 T.W. Alexander Dr., Bldg 101, Rm. D240, Research Triangle Park, North Carolina 27709, USA. E-mail: kleeber1{at}niehs.nih.gov

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

Key Words: antioxidant • reactive oxygen species • ALI • acute respiratory distress syndrome • trauma • oxidative stress • translational

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