NFE2L2 pathway polymorphisms and lung function decline in chronic obstructive pulmonary disease

Abstract

An oxidant-antioxidant imbalance in the lung contributes to the development of chronic obstructive pulmonary disease (COPD) that is caused by a complex interaction of genetic and environmental risk factors. Nuclear erythroid 2-related factor 2 (NFE2L2 or NRF2) is a critical molecule in the lung's defense mechanism against oxidants. We investigated whether polymorphisms in the NFE2L2 pathway affected the rate of decline of lung function in smokers from the Lung Health Study (LHS)(n ϭ 547) and in a replication set, the Vlagtwedde-Vlaardingen cohort (n ϭ 533). We selected polymorphisms in NFE2L2 in genes that positively or negatively regulate NFE2L2 transcriptional activity and in genes that are regulated by NFE2L2. Polymorphisms in 11 genes were significantly associated with rate of lung function decline in the LHS. One of these polymorphisms, rs11085735 in the KEAP1 gene, was previously shown to be associated with the level of lung function in the Vlagtwedde-Vlaardingen cohort but not with decline of lung function. Of the 23 associated polymorphisms in the LHS, only rs634534 in the FOSL1 gene showed a significant association in the Vlagtwedde-Vlaardingen cohort with rate of lung function decline, but the direction of the association was not consistent with that in the LHS. In summary, despite finding several nominally significant polymorphisms in the LHS, none of these associations were replicated in the Vlagtwedde-Vlaardingen cohort, indicating lack of effect of polymorphisms in the NFE2L2 pathway on the rate of decline of lung function. genetic polymorphism; nuclear erythroid 2-related factor 2; forced expiratory volume in one second CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) is the result of a complex interaction of genetic and environmental risk factors (51) and is characterized by irreversible airflow obstruction that results from chronic inflammation and tissue remodeling. Although the main environmental risk factor for COPD is cigarette smoking, longitudinal studies show that only a minority of long-term cigarette smokers develops airflow limitation (15), suggesting that additional environmental and/or genetic factors are important. Family and twin studies have demonstrated that genetic factors play a key role in the etiology of COPD (41, 49). Furthermore, genome-wide association studies of lung function (19,46,50,58,63), COPD (8, 47), and emphysema (32) have identified several putative loci underlying these traits.Several lines of evidence suggest that oxidant-antioxidant imbalance in the lung plays a major role in the pathogenesis of COPD. A measure of oxidative stress in the blood (thiobarbituric acid-reactive substances) was shown to correlate inversely with lung function in a population study (53). In addition, reactive oxygen species released by circulating neutrophils play a role in the development of airflow limitation (38). Furthermore, antioxidant nutrients have been associated with preservation of lung function (28, 42).Nuclear erythroid 2-related factor 2 (NFE2L2 or NRF2) is a basic leucine z...

Role of the Nrf2 signaling system in health and disease

“…There are a wide variety of ARE-dependent genes, including ones that encode several antioxidant, detoxification, and NADPH enzymes (33). Some relevant disease examples (Table 1) include neurodegenerative conditions such as Parkinson's disease and Huntington's disease (38)(39)(40)(41)(42), amyotrophic lateral sclerosis (43), multiple sclerosis (44,45), cancer (11,46), diabetes (47), heart disease (48), kidney diseases (49,50), lung disorders (36,(51)(52)(53)(54)(55), liver diseases (56,57), and viruses (58,59). Notably, this type of Nrf2-dependent upregulation of cytoprotective genes has been shown to increase protection against a variety of oxidative stresses (34)(35)(36)(37).…”

Role of Transcription Factors in the Pathogenesis of Asthma and COPD

“…Treatment with sulforaphane, a small-molecule activator of NRF2 is able to denitrosylate HDAC2, restoring glucocorticoid sensitivity in alveolar macrophages obtained from patients with stable COPD (Malhotra et al, 2011), suggesting the potential role of NRF2 activators for the treatment of COPD (Barnes, 2012b;Boutten et al, 2011). However, large genetic studies have been unable to fi nd a signifi cant association between polymorphisms in the NRF2 pathway and the rate of decline of lung function (Sandford et al, 2012) and the antibody used in the previous studies performed using COPD tissues does not appear to be specifi c for NRF2 (Lau et al, 2013) suggesting the necessity of further human studies in this area using validated specifi c antibodies.…”

Lung function decline over 25 years of follow-up among black and white adults in the ARIC study cohort

“…Similar methods have not been applied to the study of decline of lung function with age. To date, epidemiologic studies of rates of lung function decline have focused largely on describing discrepancies between estimates generated using cross-sectional versus longitudinal data [11–13], assessing modification of the effects of smoking on lung function decline [14–17], and evaluating associations between genetic variation and lung function decline [18,19]. While one study examined lung function declines leading to COPD [20] and several have examined differences in lung function decline by race, sex, and smoking status [12,13,17], longitudinal studies have not generally accounted for the potential influences of dropout during study follow-up.…”