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Introduction
Cigarette smoking (CS) is the main etiology of chronic obstructive pulmonary disease (COPD) and lung cancer. They share a common environmental risk factor in CS exposure and a genetic predisposition (1), as indicated by the fact that 15–30% of smokers developed COPD or lung cancer (2). Fifty to 80% of lung cancer patients have pre-existing COPD, compared with a 15–20% prevalence of COPD in the general smoking population (3–5). Findings of previous studies demonstrated that smokers with COPD are at an increased risk for developing lung cancer (6,7). Even a small reduction in forced expiratory volume in one second (FEV1), a marker of airflow obstruction, constitutes a significant predictor of lung cancer (8). Findings of a previous study suggested that in chronic smokers, airflow limitation (or reduced FEV1) is a strongly genetically determined response to CS (9). The contribution of genetic factors to the variance in FEV1 might therefore be much greater than that from CS exposure dose (10).
Nuclear factor (erythroid derived 2)-like 2 (NRF2, gene name designated as NFE2L2), is a master transcriptional activator of genes encoding numerous cytoprotective enzymes that are induced in response to environmental and endogenously derived oxidative/electrophilic agents (11–13). Oxidative stress is able to amplify the inflammatory response and the loss of NRF2 activity in COPD lungs may contribute to the increased susceptibility of COPD patients to lung cancer by regulating the expression of numerous anti-oxidant and detoxifying enzymes, thereby enhancing lung inflammation (14,15). In animal models, NRF2 plays an important role in reducing inflammation associated with elastase-induced emphysema (16). Attenuation of NRF2 due to the downregulation of the NRF2 mRNA has been detected in alveolar macrophages of COPD patients (17). Single-nucleotide polymorphisms (SNPs) in the promoter region of NRF2 gene affect transcriptional activity. Additionally, one of the SNPs is associated with the development of acute lung injury (18). NRF2 gene promoter SNP has been identified to be potentially correlated with carcinogenesis (19). The SNP rs2364723 in the first intron of NRF2 gene has been shown to correlate with a lower FEV1 in a Caucasian population (20). Association between another the NRF2 SNP rs6726395 and smoking status affected the annual decline in FEV1 in a Japanese cohort (21).
To analyze the association between the NRF2 SNPs and FEV1...