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

    Published Online:ericyue.info/10.1096/fj.06-7759com

    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.


    • 1 Goss, C. H., Brower, R. G., Hudson, L. D., Rubenfield, G. D. (2003) Incidence of acute lung injury in the United States. Crit. Care. Med. 31,1607-1611 Crossref Medline
    • 2 Repine, J. E. (1992) Scientific perspectives on adult respiratory distress syndrome. Lancet 339,466-469 Crossref Medline
    • 3 Louie, S., Halliwell, B., Cross, C. E. (1997) Adult respiratory distress syndrome: a radical perspective. Adv. Pharmacol. 38,457-490 Medline
    • 4 Gadek, J. E., Pacht, E. R. (1996) The interdependence of lung antioxidants and antiprotease defense in ARDS. Chest 110,273S-277S Crossref Medline
    • 5 Al-Mehdi, A. B., Zhao, G., Dodia, C., Tozawa, K., Costa, K., Muzykantov, V., Ross, C., Blecha, F., Dinauer, M., Fisher, A. B. (1998) Endothelial NADPH oxidase as the source of oxidants in lungs exposed to ischemia or high K+. Circ. Res. 83,730-737 Crossref Medline
    • 6 Fridovich, I. (1978) The biology of oxygen radicals. Science 201,875-880 Crossref Medline
    • 7 Moss, M., Bucher, B., Moore, F. A., Moore, E. E., Parsons, P. E. (1996) The role of chronic alcohol abuse in the development of acute respiratory distress syndrome in adults. JAMA 275,50-54 Crossref Medline
    • 8 Moss, M., Guidot, D. M., Steinberg, K. P., Duhon, G. F., Treece, P., Wolken, R., Hudson, L. D., Parsons, P. E. (2000) Diabetic patients have a decreased incidence of acute respiratory distress syndrome. Crit. Care. Med. 28,2187-2192 Crossref Medline
    • 9 Matthay, M., Zimmerman, G. A., Esmon, C., Bhattacharya, J., Coller, B., Doerschuk, C. M., Floros, J., Gimbrone, M. A., Jr, Hoffman, E., Hubmayr, R. D., et al (2003) Future research directions in acute lung injury: summary of a national heart, lung and blood institute working group. Am. J. Respir. Crit. Care Med. 167,1027-1035 Crossref Medline
    • 10 Cho, H., Jedlicka, A. E., Reddy, S. P., Zhang, L. Y., Kensler, T. W., Kleeberger, S. R. (2002) Linkage analysis of susceptibility to hyperoxia: Nrf2 is a candidate gene. 2002. Am. J. Respir. Cell Mol. Biol. 26,42-51 Crossref Medline
    • 11 Cho, H., Jedlicka, A. E., Reddy, S. P., Kensler, T. W., Yamamoto, M., Zhang, L. Y., Kleeberger, S. R. (2002) Role of NRF2 in protection against hyperoxic lung injury in mice. Am. J. Respir. Cell Mol. Biol. 26,175-182 Crossref Medline
    • 12 Itoh, K., Wakabayashi, N., Katoh, Y., Ishii, T., Igarashi, K., Engel, J. D., Yamamoto, M. (1999) Keap1 represses nuclear activation of antioxidant responsive elements by Nrf2 through binding to the amino-terminal Neh2 domain. Genes Develop. 13,76-86 Crossref Medline
    • 13 Itoh, K., Tong, K. I., Yamamoto, M. (2004) Molecular mechanism activating Nrf2-Keap1 pathway in regulation of adaptive response to electrophiles. Free. Radic. Biol. Med. 36,1208-1213 Crossref Medline
    • 14 Itoh, K., Igarashi, K., Hayashi, N., Nishizawa, M., Yamamoto, M. (1995) Cloning and characterization of a novel erythroid cell-derived CNC family transcription factor heterodimerizing with the small Maf family proteins. Mol. Cell. Biol. 15,4184-4193 Crossref Medline
    • 15 Cho, H. Y., Reddy, S. P., DeBiase, A., Yamamoto, M., Kleeberger, S. R. (2005) Gene expression profiling of NRF2-mediated protection against oxidative injury. Free. Radic. Biol. Med. 38,325-343 Crossref Medline
    • 16 Kruglyak, L., Nickerson, D. A. (2001) Variation is the spice of life. Nat. Genet. 27,234-236 Crossref Medline
    • 17 Patterson, T., Vuong, H., Liaw, Y. S., Wu, R., Kalvakolnu, D. V., Reddy, S. P. (2001) Mechanism of repression of squamous differentiation marker, SPRR1B, in malignant bronchial epithelial cells: role of critical TRE-sites and its transacting factors. Oncogene 20,634-644 Crossref Medline
    • 18 Civil, I. D., Schwab, C. W. (1988) The abbreviated injury scale. 1985 revision: a condensed chart for clinical use. J. Trauma 28,87-90 Crossref Medline
    • 19 Bernard, G., Artigas, A., Brigham, K. L., Carlet, J., Falke, K., Hudson, L., Lamy, M., Legall, J. R., Morris, A., Spragg, R. (1994) The American European consensus conference on ARDS: definitions, mechanisms, relevant outcomes, and clinical trials coordination. Am. J. Respir. Crit. Care. Med. 149,818-824 Crossref Medline
    • 20 Mander, A. (2000) Haplotype frequency estimation using an EM algorithm and log-linear modeling. Stata Techn. Bull. 57,5-7
    • 21 Terwilliger, J., Ott, J. (1994) Handbook of Human Genetic Linkage Johns Hopkins Univ. Press Baltimore, MD, U. S. A..
    • 22 Knaus, W. A., Draper, E. A., Wagner, D. P., Zimmerman, J. E. (1985) APACHE II: a severity of disease classification system. Crit. Care. Med. 13,818-829 Crossref Medline
    • 23 Heinemeyer, T., Wingender, E., Reuter, I., Hermjakob, H., Kel, A. E., Kel, O. V., Ignatieva, E. V., Ananko, E. A., Podkolodnaya, O. A., Kolpakov, F. A., et al (1998) Databases on transcriptional regulation: TRANSFAC, TRRD and COMPEL. Nuc. Acids. Res. 26,362-367 Crossref Medline
    • 24 Robertson, K.A., Hill, D.P., Kelley, M.R., Tritt, R., Crum, B., Van Epps, S., Srour, E., Rice, S., Hromas, R. (1998) The myeloid zinc finger gene (MZF1) delays retinoic acid-induced apoptosis and differentiation in myeloid leukemia cells. Leukemia 12,690-698 Crossref Medline
    • 25 Mossman, B. T., Reddy, S. P. (2002) Role and regulation of activator protein-1 in toxicant-induced responses of the lung. Am. J. Physiol. Lung Cell Mol. Physiol. 283,L1161-L1178 Crossref Medline
    • 26 Kwak, M. K., Itoh, K., Yamamoto, M., Kensler, T. W. (2002) Enhanced expression of the transcription factor Nrf2 by cancer chemopreventive agents: role of antioxidant response element-like sequences in the nrf2 promoter. Mol. Cell. Biol. 22,2883-2892 Crossref Medline
    • 27 Lin, Z., Pearson, C., Chinchilli, V., Pietschmann, S. M., Luo, J., Pison, U., Floros, J. (2000) Polymorphisms of human SP-A, SP-B, and SP-D genes: association of SP-B Thr131Ile with ARDS. Clin. Genet. 58,181-191 Medline
    • 28 Marshall, R. P., Webb, S., Bellingan, G. J., Montgomery, H. E., Chaudhari, B., McAnulty, R. J., Humphries, S. E., Hill, M. R., Laurent, G. J. (2002) Angiotensin converting enzyme insertion/deletion polymorphism is associated with susceptibility and outcome in acute respiratory distress syndrome. Am. J. Respir. Crit. Care. Med. 166,646-650 Crossref Medline
    • 29 Olofsson, P., Holmberg, J., Tordsson, J., Lu, S., Akerstrom, B., Holmdahl, R. (2003) Positional cloning of Ncf1 as a gene that regulates arthritis severity in rats. Nat. Genet. 33,25-32 Crossref Medline
    • 30 Hou, X., Mrug, M., Yoder, B. K., Lefkowitz, E. J., Kremmidiotis, G., D’Eustachio, P., Beier, D. R., Guay-Woodford, L. M. (2002) Cystin, a novel cilia-associated protein, is disrupted in the cpk mouse model of polycystic kidney disease. J. Clin. Invest. 109,533-540 Crossref Medline
    • 31 Lam-Yuk-Tseung, S., Gros, P. (2003) Genetic control of susceptibility to bacterial infections in mouse models. Cell. Microbiol. 5,299-313 Crossref Medline
    • 32 Poltorak, A., He, X., Smirnova, I., Liu, M. Y., Van Huffel, C., Du, X., Birdwell, D., Alejos, E., Silva, M., Galanos, C., et al (1998) Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. Science 282,2085-2088 Crossref Medline
    • 33 Aoki, Y., Sato, H., Nishimura, N., Takahashi, S., Itoh, K., Yamamoto, M. (2001) Accelerated DNA adduct formation in the lung of the Nrf2 knockout mouse exposed to diesel exhaust. Toxicol. Appl. Pharmacol. 173,154-160 Crossref Medline
    • 34 Chan, K., Kan, Y. W. (1999) Nrf2 is essential for protection against acute pulmonary injury in mice. Proc. Natl. Acad. Sci. U. S. A. 96,12731-12736 Crossref Medline
    • 35 Cho, H., Reddy, S. P. M., Yamamoto, M., Kleeberger, S. R. (2004) The transcription factor NRF2 protects against pulmonary fibrosis. FASEB J. 18,1258-1260
    • 36 Yamamoto, T., Yoh, K., Kobayashi, A., Ishii, Y., Kure, S., Koyama, A., Sakamoto, T., Sekizawa, K., Motohashi, H., Yamamoto, M. (2004) Identification of polymorphisms in the promoter region of the human NRF2 gene. Biochem. Biophys. Res. Commun. 321,72-79 Crossref Medline
    • 37 Alam, J., Stewart, D., Touchard, C., Boinapally, S., Choi, A. M., Cook, J. L. (1999) Nrf2, a cap‘n’collar transcription factor, regulates induction of the heme oxygenase-1 gene. J. Biol. Chem. 274,26071-26078 Crossref Medline
    • 38 Chan, K., Lu, R., Chang, J. C., Kan, Y. W. (1999) Nrf2, a member of NFE2 family of transcription factors, is not essential for murine erythropoiesis, growth and development. Proc. Natl. Acad. Sci. U. S. A. 93,13943-13948
    • 39 Venugopal, R., Jaiswal, A. K. (1998) Nrf2 and Nrf1 in association with Jun proteins regulate the antioxidant response element-mediated expression and coordinated induction of genes encoding detoxifying enzymes. Oncogene 17,3145-3156 Crossref Medline
    • 40 Ramos-Gomez, M., Kwak, M. K., Dolan, P. M., Itoh, K., Yamamoto, M., Talalay, P., Kensler, T. W. (2001) Sensitivity to carcinogenesis is increased and chemoprotective efficacy of enzyme inducers is lost in nrf2 transcription factor-deficient mice. Proc. Natl. Acad. Sci. U. S. A. 98,3410-3415 Crossref Medline
    • 41 Chan, K., Kan, Y. W. (1999) Nrf2 is essential for protection against acute pulmonary injury in mice. Proc. Natl. Acad. Sci. U. S. A. 96,12731-12736 Crossref Medline
    • 42 Halliwell, B., Gutteridge, J. M., Cross, C. E. (1992) Free radicals, antioxidants, and human disease: where are we now?. J. Lab. Clin. Med. 119,598-620 Medline
    • 43 Justice, A. C., Covinsky, K. E., Berlin, J. A. (1999) Assessing the generalizability of prognostic information. Ann. Intern. Med. 130,515-524 Crossref Medline
    • 44 Kanetsky, P. A., Holmes, R., Walker, A., Najarian, D., Swoyer, J., Guerry, D., Halpern, A., Rebbeck, T. R. (2001) Interaction of glutathione S-transferase M1 and T1 genotypes and malignant melanoma. Cancer Epidemiol. Biomarkers Prev. 10,509-513 Medline
    • 45 Rebbeck, T. R., Walker, A. H., Jaffe, J. M., White, D. L., Wein, A. J., Malkowicz, S. B. (1999) Glutathione S-transferase-mu (GSTM1) and –theta (GSTT1) genotypes in the etiology of prostate cancer. Cancer Epidemiol. Biomarkers Prev. 8,283-287 Medline
    • 46 Wang, Y., Localio, R., Rebbeck, T. R. (2004) Evaluating bias due to population stratification in case-control association studies of admixed populations. Genet. Epidemiol. 27,14-20 Crossref Medline


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