Abstract
Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) protects against oxidative stress which is important in the pathogenesis of chronic obstructive pulmonary disease (COPD). Three single nucleotide polymorphisms and 1 triplet repeat polymorphism are found in the promoter region of theNrf2gene. Molecular haplotyping of theNrf2promoter region was performed using DNA obtained from the peripheral blood of 69 COPD patients. The luciferase activities ofNrf2promoter constructs containing all possible combinations of the 4 polymorphisms were determined and found to differ among the 16 haplotypes.The haplotypes isolated from the subjects were divided into 3 groups (L: low; M: medium; H: high) on the basis of luciferase activities. The proportions of subjects belonging to global initiative for chronic obstructive lung disease stage 3 or 4 decreased from the group with the LL haplotype to that with the HH haplotype. Presence of the LH or MM haplotype (hazard ratio, 3.36; 95% confidence interval, 1.16–9.69), gender (0.13; 0.02–0.67), and post-bronchodilator FEV1value of predicted (0.95; 0.91–0.99) are significant predictors of respiratory failure development.The haplotype of theNrf2gene promoter affects its activity, and is associated with the severity and the development of respiratory failure in COPD.
Highlights
Chronic obstructive pulmonary disease (COPD) is an inflammatory lung disease characterized by systemic and chronic localized inflammation induced by oxidative stress [1]
This study examines the luciferase activities of constructs containing all possible combinations of the 4 polymorphisms in the promoter region of the Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) gene and determines the distribution of haplotypes in COPD patients
The haplotype constituted by the 3 SNPs and 1 triplet repeat polymorphism affects the luciferase activity of the Nrf2 gene promoter
Summary
Chronic obstructive pulmonary disease (COPD) is an inflammatory lung disease characterized by systemic and chronic localized inflammation induced by oxidative stress [1]. Oxidative stress regulates both signal transduction and histone modification in lung inflammation. Reactive oxygen species (ROS) generated as a result of oxidative stress enhance inflammation by activating stress kinases and redox-sensitive transcription factors [2]. In COPD, levels of ROS increase while those of antioxidant enzymes decrease, and the imbalance between oxidative stress and endogenous antioxidant mechanisms results in chronic inflammation [1]. The Nrf2-Keap system is one of the major cellular defense mechanisms
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