Functional Haplotypes in the Promoter Region of Transcription FactorNrf2in Chronic Obstructive Pulmonary Disease

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 the Nrf2 gene. Molecular haplotyping of the Nrf2 promoter region was performed using DNA obtained from the peripheral blood of 69 COPD patients. The luciferase activities of Nrf2 promoter 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 FEV1 value of predicted (0.95; 0.91–0.99) are significant predictors of respiratory failure development.The haplotype of the Nrf2 gene promoter affects its activity, and is associated with the severity and the development of respiratory failure in COPD.

Viral-mediated Inhibition of Antioxidant Enzymes Contributes to the Pathogenesis of Severe Respiratory Syncytial Virus Bronchiolitis

“…More severe RSV disease, including higher viral titers, augmented inflammation, and enhanced mucus production and epithelial injury, were found in Nrf2 2/2 mice compared with Nrf2 1/1 mice. Significant down-regulation of Nrf2 mRNA expression has been observed in pulmonary macrophages of aged smokers and patients with COPD (49), and functional polymorphisms in the Nrf2 gene promoter, leading to reduced gene transcription, are associated with the severity of COPD (50) and increased risk of acute lung injury after trauma (51).…”

A Preliminary Study on Racial Differences in HMOX1, NFE2L2, and TGFβ1 Gene Polymorphisms and Radiation-Induced Late Normal Tissue Toxicity

“…The NFE2L2 promoter SNPS were studied as described (22). The HO-1 GT repeat domain was isolated by PCR using the sense primer, 5’-AGAGCCTGCAGCT... TCTCAGA-3’ and for the antisense primer, 5’-[6-FAM]AGAGCC...GCAGCTTCTCAGA-3’.…”

Transcription Factor NRF2 as a Therapeutic Target for Chronic Diseases: A Systems Medicine Approach

“…Decreased NRF2 expression is associated with increased macrophage expression of the lipid peroxidation product 4-hydroxynonenal. In the NFE2L2 promoter, a functional haplotype constituted by three SNPs and one triplet repeat, polymorphism that produces low to medium NRF2 expression , was associated with increased risk to develop COPD (Hua et al, 2010). The low-expressing haplotypes were significant predictors for developing respiratory failure.…”