Functional polymorphisms in the transcription factor NRF2 in humans increase the risk of acute lung injury.
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
Jacqui M
JM
Laboratory of Respiratory Biology, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709, USA.
Christie
Jason D
JD
Reddy
Sekhar P
SP
Jedlicka
Anne E
AE
Vuong
Hue
H
Lanken
Paul N
PN
Aplenc
Richard
R
Yamamoto
Tae
T
Yamamoto
Masayuki
M
Cho
Hye-Youn
HY
Kleeberger
Steven R
SR
D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D001483:Base Sequence; D016022:Case-Control Studies; D002460:Cell Line; D002889:Chromosomes, Human, Pair 2 / Q000235:genetics; D024202:Electrophoretic Mobility Shift Assay; D005006:Ethnicity / Q000235:genetics; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology; D017930:Genes, Reporter; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008297:Male; D051379:Mice; D008875:Middle Aged; D008969:Molecular Sequence Data; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000502:physiology*; D018384:Oxidative Stress; D020641:Polymorphism, Single Nucleotide; D012128:Respiratory Distress Syndrome / Q000209:etiology / Q000235:genetics*; D013045:Species Specificity
D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human