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Lung cancer is the leading cause of cancer death worldwide and nearly 90% of cases are attributable to smoking. Quitting smoking and early diagnosis of lung cancer, through computed tomographic screening, are the only ways to reduce mortality from lung cancer. Recent epidemiological studies show that risk prediction for lung cancer is optimized by using multivariate risk models that include age, smoking exposure, history of chronic obstructive pulmonary disease (COPD), family history of lung cancer, and body mass index. It has also been shown that COPD predates lung cancer in 65–70% of cases, conferring a four- to sixfold greater risk of lung cancer compared to smokers with normal lung function. Genome-wide association studies of smokers have identified a number of genetic variants associated with COPD or lung cancer. In a case–control study, where smokers with normal lungs were compared to smokers who had spirometry-defined COPD or histology confirmed lung cancer, several of these variants were shown to overlap, conferring the same susceptibility or protective effects on both COPD and lung cancer (independent of COPD status). In this perspective article, we show how combining clinical data with genetic variants can help identify heavy smokers at the greatest risk of lung cancer. Using this approach, we found that gene-based risk testing helped engage smokers in risk mitigating activities like quitting smoking and undertaking lung cancer screening. We suggest that such an approach could facilitate the targeted selection of smokers for cost-effective life-saving interventions.

Lung cancer continues to be the leading cause of cancer death, and although most lung cancer is attributable to cigarette smoking, underlying genetic susceptibility is suggested by studies demonstrating familial aggregation. The first family linkage study of lung cancer has identified linkage of lung, laryngeal, and pharyngeal cancer in families to a region on chromosome 6q23–25. Because lung cancer and chronic obstructive pulmonary disease (COPD) are known to aggregate in families beyond shared risk associated with smoking, the linkage results are compared and contrasted with results from genomewide linkage and association studies and candidate gene studies searching for genes for lung cancer, lung function, and COPD. Linkage on chromosome 6q to both lung cancer and lung function, and on 12 to lung cancer, COPD, and lung function, together with overlap in candidate genes for these outcomes, suggests that future research into underlying genetic mechanisms of lung disease would benefit from broadening the collection of family history data and better defining the “high risk” population. As familial risk of lung disease is better defined, referral into screening programs and prevention trials can be better targeted to reach families with both a history of lung cancer and COPD.

Background

We have previously identified Urokinase Plasminogen Activator Receptor (PLAUR) as an asthma susceptibility gene. In the current study we tested the hypothesis that PLAUR single nucleotide polymorphisms (SNPs) determine baseline lung function and contribute to the development of Chronic Obstructive Pulmonary Disease (COPD) in smokers.

Methods

25 PLAUR SNPs were genotyped in COPD subjects and individuals with smoking history (n = 992). Linear regression was used to determine the effects of polymorphism on baseline lung function (FEV1, FEV1/FVC) in all smokers. Genotype frequencies were compared in spirometry defined smoking controls (n = 176) versus COPD cases (n = 599) and COPD severity (GOLD stratification) using logistic regression.

Results

Five SNPs showed a significant association (p < 0.01) with baseline lung function; rs2302524(Lys220Arg) and rs2283628(intron 3) were associated with lower and higher FEV1 respectively. rs740587(-22346), rs11668247(-20040) and rs344779(-3666) in the 5'region were associated with increased FEV1/FVC ratio. rs740587 was also protective for COPD susceptibility and rs11668247 was protective for COPD severity although no allele dose relationship was apparent. Interestingly, several of these associations were driven by male smokers not females.

Conclusion

This study provides tentative evidence that the asthma associated gene PLAUR also influences baseline lung function in smokers. However the case-control analyses do not support the conclusion that PLAUR is a major COPD susceptibility gene in smokers. PLAUR is a key serine protease receptor involved in the generation of plasmin and has been implicated in airway remodelling.

Cachexia, whether assessed by body mass index (BMI) or fat-free mass index (FFMI), affects a significant proportion of patients with chronic obstructive pulmonary disease (COPD), and is an independent risk factor for increased mortality, increased emphysema, and more severe airflow obstruction. The variable development of cachexia among patients with COPD suggests a role for genetic susceptibility. The objective of the present study was to determine genetic susceptibility loci involved in the development of low BMI and FFMI in subjects with COPD. A genome-wide association study (GWAS) of BMI was conducted in three independent cohorts of European descent with Global Initiative for Chronic Obstructive Lung Disease stage II or higher COPD: Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-Points (ECLIPSE; n = 1,734); Norway-Bergen cohort (n = 851); and a subset of subjects from the National Emphysema Treatment Trial (NETT; n = 365). A genome-wide association of FFMI was conducted in two of the cohorts (ECLIPSE and Norway). In the combined analyses, a significant association was found between rs8050136, located in the first intron of the fat mass and obesity–associated (FTO) gene, and BMI (P = 4.97 × 10−7) and FFMI (P = 1.19 × 10−7). We replicated the association in a fourth, independent cohort consisting of 502 subjects with COPD from COPDGene (P = 6 × 10−3). Within the largest contributing cohort of our analysis, lung function, as assessed by forced expiratory volume at 1 second, varied significantly by FTO genotype. Our analysis suggests a potential role for the FTO locus in the determination of anthropomorphic measures associated with COPD.

Introduction

Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease with pulmonary and extra-pulmonary manifestations. Although COPD is a complex disease, diagnosis and staging are still based on simple spirometry measurements. Different COPD phenotypes exist based on clinical, physiological, immunological and radiological observations. Cigarette smoking is the most important risk factor for COPD, but only 15–20% of smokers develop the disease, suggesting a genetic predisposition. Unfortunately, little is known about the pathogenesis of COPD, and even less on the very first steps that are associated with an aberrant response to smoke exposure. This study aims to investigate the underlying local and systemic inflammation of different clinical COPD phenotypes, and acute effects of cigarette smoke exposure in individuals susceptible and non-susceptible for the development of COPD. Furthermore, we will investigate mechanisms associated with corticosteroid insensitivity. Our study will provide valuable information regarding the pathogenetic mechanisms underlying the natural course of COPD.

Methods and analysis

This cross-sectional study will include young and old individuals susceptible or non-susceptible to develop COPD. At a young age (18–40 years) 60 ‘party smokers’ will be included who are called susceptible or non-susceptible based on COPD prevalence in smoking family members. In addition, 30 healthy smokers (age 40–75 years) and 110 COPD patients will be included. Measurements will include questionnaires, pulmonary function, low-dose CT scanning of the lung, body composition, 6 min walking distance and biomarkers in peripheral blood, sputum, urine, exhaled breath condensate, epithelial lining fluid, bronchial brushes and biopsies. Non-biased approaches such as proteomics will be performed in blood and epithelial lining fluid.

Ethics and dissemination

This multicentre study was approved by the medical ethical committees of UMC Groningen and Utrecht, the Netherlands. The study findings will be presented at conferences and will be reported in peer-reviewed journals.

Trial registration

ClinicalTrials.gov, NCT00807469 (study 1) and NCT00850863 (study 2).

Cigarette smoke has been connected to an array of chronic lung diseases and is a major source of morbidity and mortality. Active smoking is responsible for approximately 90% of lung cancer cases. In addition, cigarette smoke is associated with other chronic pulmonary diseases such as pulmonary edema, chronic bronchitis, and pulmonary emphysema, the last two also termed chronic obstructive pulmonary disease (COPD). Lung cancer and COPD are developed very frequently in chronic cigarette smokers. It has been known for some time that lung cancer incidence increases in patients with COPD. Even the existence of some low-grade emphysema without noticeable airflow obstruction is associated with significantly elevated risk of lung cancer. These recent clinical insights demand new thinking and exploration of novel mechanistic studies to fully understand these observations. Lung injury and repair involve cell death and hyperplasia of airway epithelial cells and infiltration of inflammatory cells. All of these occur simultaneously. The mechanisms of cell death and hyperplasia in the lung constitute two sides of the coin of lung injury and repair. However, most molecular studies in airway epithelial cells center on the mechanism(s) of either cell growth and proliferation or cell death and the ceramide-generating machinery that drives aberrant induction of apoptotic cell death. Very few address both sides of the coin as an outcome of cigarette smoke exposure, which is the focus of this review.

Lung cancer is the leading cause of cancer deaths in the United States. In addition to genetic abnormalities induced by cigarette smoke, several epidemiologic studies have found that smokers with chronic obstructive pulmonary disease (COPD), an inflammatory disease of the lungs, have an increased risk of lung cancer (1.3- to 4.9-fold) compared to smokers without COPD. This suggests a link between chronic airway inflammation and lung carcinogenesis, independent of tobacco smoke exposure. We studied this association by assaying the inflammatory impact of products of nontypeable Haemophilus influenzae, which colonizes the airways of patients with COPD, on lung cancer promotion in mice with an activated K-ras mutation in their airway epithelium. Two new mouse models of lung cancer were generated by crossing mice harboring the LSL–K-rasG12D allele with mice containing Cre recombinase inserted into the Clara cell secretory protein (CCSP) locus, with or without the neomycin cassette excised (CCSPCre and CCSPCre-Neo, respectively). Lung lesions in CCSPCre-Neo/LSL–K-rasG12D and CCSPCre/LSL–K-rasG12D mice appeared at 4 and 1 month of age, respectively, and were classified as epithelial hyperplasia of the bronchioles, adenoma, and adenocarcinoma. Weekly exposure of CCSPCre/LSL–K-rasG12D mice to aerosolized nontypeable Haemophilus influenzae lysate from age 6–14 weeks resulted in neutrophil/macrophage/CD8 T-cell–associated COPD-like airway inflammation, a 3.2-fold increase in lung surface tumor number (156 ± 9 versus 45 ± 7), and an increase in total lung tumor burden. We conclude that COPD-like airway inflammation promotes lung carcinogenesis in a background of a G12D-activated K-ras allele in airway secretory cells.

Lung cancer (LC) and chronic obstructive pulmonary disease (COPD) commonly coexist in smokers, and the presence of COPD increases the risk of developing LC. Cigarette smoke causes oxidative stress and an inflammatory response in lung cells, which in turn may be involved in COPD and lung cancer development. The aim of this study was to identify differential proteomic profiles related to oxidative stress response that were potentially involved in these two pathological entities. Protein content was assessed in the bronchoalveolar lavage (BAL) of 60 patients classified in four groups: COPD, COPD and LC, LC, and control (neither COPD nor LC). Proteins were separated into spots by two dimensional polyacrylamide gel electrophoresis (2D-PAGE) and examined by matrix-assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF/TOF). A total of 16 oxidative stress regulatory proteins were differentially expressed in BAL samples from LC and/or COPD patients as compared with the control group. A distinct proteomic reactive oxygen species (ROS) protein signature emerged that characterized lung cancer and COPD. In conclusion, our findings highlight the role of the oxidative stress response proteins in the pathogenic pathways of both diseases, and provide new candidate biomarkers and predictive tools for LC and COPD diagnosis.

The epidemiology of chronic obstructive pulmonary disease (COPD) has been dominated by one hypothesis stating that cigarette smoking and chronic bronchitis were the key to pathogenesis and another that asthma, chronic bronchitis, and even emphysema are related to different expressions of a primary airway abnormality. The first hypothesis was rejected in the late 1960s based on a longitudinal study of working men where only a fraction of smokers developed COPD and where development of COPD was independent of the absence or presence of chronic bronchitis. Chronic bronchitis in more advanced COPD was subsequently associated with a more rapid decline in lung function and more frequent exacerbations. The second hypothesis is more difficult to test but longitudinal studies have shown that the presence of bronchial hyperresponsiveness may predict the subjects who go on to develop COPD. This brief review attempts to reconcile these findings with the pathology found in the lung.

There is considerable variability in the susceptibility of smokers to develop chronic obstructive pulmonary disease (COPD). The only known genetic risk factor is severe deficiency of α1-antitrypsin, which is present in 1–2% of individuals with COPD. We conducted a genome-wide association study (GWAS) in a homogenous case-control cohort from Bergen, Norway (823 COPD cases and 810 smoking controls) and evaluated the top 100 single nucleotide polymorphisms (SNPs) in the family-based International COPD Genetics Network (ICGN; 1891 Caucasian individuals from 606 pedigrees) study. The polymorphisms that showed replication were further evaluated in 389 subjects from the US National Emphysema Treatment Trial (NETT) and 472 controls from the Normative Aging Study (NAS) and then in a fourth cohort of 949 individuals from 127 extended pedigrees from the Boston Early-Onset COPD population. Logistic regression models with adjustments of covariates were used to analyze the case-control populations. Family-based association analyses were conducted for a diagnosis of COPD and lung function in the family populations. Two SNPs at the α-nicotinic acetylcholine receptor (CHRNA 3/5) locus were identified in the genome-wide association study. They showed unambiguous replication in the ICGN family-based analysis and in the NETT case-control analysis with combined p-values of 1.48×10−10, (rs8034191) and 5.74×10−10 (rs1051730). Furthermore, these SNPs were significantly associated with lung function in both the ICGN and Boston Early-Onset COPD populations. The C allele of the rs8034191 SNP was estimated to have a population attributable risk for COPD of 12.2%. The association of hedgehog interacting protein (HHIP) locus on chromosome 4 was also consistently replicated, but did not reach genome-wide significance levels. Genome-wide significant association of the HHIP locus with lung function was identified in the Framingham Heart study (Wilk et al., companion article in this issue of PLoS Genetics; doi:10.1371/journal.pgen.1000429). The CHRNA 3/5 and the HHIP loci make a significant contribution to the risk of COPD. CHRNA3/5 is the same locus that has been implicated in the risk of lung cancer.

Author Summary

There is considerable variability in the susceptibility of smokers to develop chronic obstructive pulmonary disease (COPD), which is a heritable multi-factorial trait. Identifying the genetic determinants of COPD risk will have tremendous public health importance. This study describes the first genome-wide association study (GWAS) in COPD. We conducted a GWAS in a homogenous case-control cohort from Norway and evaluated the top 100 single nucleotide polymorphisms in the family-based International COPD Genetics Network. The polymorphisms that showed replication were further evaluated in subjects from the US National Emphysema Treatment Trial and controls from the Normative Aging Study and then in a fourth cohort of extended pedigrees from the Boston Early-Onset COPD population. Two polymorphisms in the α-nicotinic acetylcholine receptor 3/5 locus on chromosome 15 showed unambiguous evidence of association with COPD. This locus has previously been implicated in both smoking behavior and risk of lung cancer, suggesting the possibility of multiple functional polymorphisms in the region or a single polymorphism with wide phenotypic consequences. The hedgehog interacting protein (HHIP) locus on chromosome 4, which is associated with COPD, is also a significant risk locus for COPD.

Background

Chronic obstructive pulmonary disease (COPD) is a disorder associated to cigarette smoke and lung cancer (LC). Since epigenetic changes in oncogenes and tumor suppressor genes (TSGs) are clearly important in the development of LC. In this study, we hypothesize that tobacco smokers are susceptible for methylation in the promoter region of TSGs in airway epithelial cells when compared with non-smoker subjects. The purpose of this study was to investigate the usefulness of detection of genes promoter methylation in sputum specimens, as a complementary tool to identify LC biomarkers among smokers with early COPD.

Methods

We determined the amount of DNA in induced sputum from patients with COPD (n = 23), LC (n = 26), as well as in healthy subjects (CTR) (n = 33), using a commercial kit for DNA purification, followed by absorbance measurement at 260 nm. The frequency of CDKN2A, CDH1 and MGMT promoter methylation in the same groups was determined by methylation-specific polymerase chain reaction (MSP). The Fisher’s exact test was employed to compare frequency of results between different groups.

Results

DNA concentration was 7.4 and 5.8 times higher in LC and COPD compared to the (CTR) (p < 0.0001), respectively. Methylation status of CDKN2A and MGMT was significantly higher in COPD and LC patients compared with CTR group (p < 0.0001). Frequency of CDH1 methylation only showed a statistically significant difference between LC patients and CTR group (p < 0.05).

Conclusions

We provide evidence that aberrant methylation of TSGs in samples of induced sputum is a useful tool for early diagnostic of lung diseases (LC and COPD) in smoker subjects.

Virtual slides

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Rationale: Wood smoke–associated chronic obstructive pulmonary disease (COPD) is common in women in developing countries but has not been adequately described in developed countries.

Objectives: Our objective was to determine whether wood smoke exposure was a risk factor for COPD in a population of smokers in the United States and whether aberrant gene promoter methylation in sputum may modify this association.

Methods: For this cross-sectional study, 1,827 subjects were drawn from the Lovelace Smokers' Cohort, a predominantly female cohort of smokers. Wood smoke exposure was self-reported. Postbronchodilator spirometry was obtained, and COPD outcomes studied included percent predicted FEV1, airflow obstruction, and chronic bronchitis. Effect modification of wood smoke exposure with current cigarette smoke, ethnicity, sex, and promoter methylation of lung cancer-related genes in sputum on COPD outcomes were separately explored. Multivariable logistic and poisson regression models were used for binary and rate-based outcomes, respectively.

Measurements and Main Results: Self-reported wood smoke exposure was independently associated with a lower percent predicted FEV1 (point estimate [± SE] −0.03 ± 0.01) and a higher prevalence of airflow obstruction and chronic bronchitis (odds ratio, 1.96; 95% confidence interval, 1.52–2.52 and 1.64 (95% confidence interval, 1.31–2.06, respectively). These associations were stronger among current cigarette smokers, non-Hispanic whites, and men. Wood smoke exposure interacted in a multiplicative manner with aberrant promoter methylation of the p16 or GATA4 genes on lower percent predicted FEV1.

Conclusions: These studies identify a novel link between wood smoke exposure and gene promoter methylation that synergistically increases the risk for reduced lung function in cigarette smokers.

Chronic Obstructive Pulmonary Disease (COPD) is a strong risk factor for lung cancer. Published studies regarding variations of genes encoding glutathione metabolism, DNA repair, and inflammatory response pathways in susceptibility to COPD were inconclusive.

We evaluated 470 single nucleotide polymorphisms (SNPs) from 56 genes of these 3 pathways in 620 cases and 893 controls to identify susceptibility markers for COPD risk, using existing resources. We assessed SNP- and gene-level effects adjusting for sex, age, and smoking status. Differential genetic effects on disease risk with and without lung cancer were also assessed; cumulative risk models were established.

Twenty-one SNPs were found to be significantly associated with risk of COPD (P<0.01); gene-based analyses confirmed 2 genes (GCLC and GSS) and identified 3 additional (GSTO2, ERCC1, and RRM1). Carrying 12 high-risk alleles may increase risk by 2.7-fold; 8 SNPs altered COPD risk with lung cancer 3.1-fold, and 4 SNPs altered the risk without lung cancer 2.3-fold.

Our findings indicate that multiple genetic variations in the 3 selected pathways contribute to COPD risk through GCLC, GSS, GSTO2, ERCC1, and RRM1 genes. Functional studies are needed to elucidate the mechanisms of these genes in the development of COPD, lung cancer, or both.

Rationale: Chromosome 12p has been linked to chronic obstructive pulmonary disease (COPD) in the Boston Early-Onset COPD Study (BEOCOPD), but a susceptibility gene in that region has not been identified.

Objectives: We used high-density single-nucleotide polymorphism (SNP) mapping to implicate a COPD susceptibility gene and an animal model to determine the potential role of SOX5 in lung development and COPD.

Methods: On chromosome 12p, we genotyped 1,387 SNPs in 386 COPD cases from the National Emphysema Treatment Trial and 424 control smokers from the Normative Aging Study. SNPs with significant associations were then tested in the BEOCOPD study and the International COPD Genetics Network. Based on the human results, we assessed histology and gene expression in the lungs of Sox5−/− mice.

Measurements and Main Results: In the case-control analysis, 27 SNPs were significant at P ≤ 0.01. The most significant SNP in the BEOCOPD replication was rs11046966 (National Emphysema Treatment Trial–Normative Aging Study P = 6.0 × 10−4, BEOCOPD P = 1.5 × 10−5, combined P = 1.7 × 10−7), located 3′ to the gene SOX5. Association with rs11046966 was not replicated in the International COPD Genetics Network. Sox5−/− mice showed abnormal lung development, with a delay in maturation before the saccular stage, as early as E16.5. Lung pathology in Sox5−/− lungs was associated with a decrease in fibronectin expression, an extracellular matrix component critical for branching morphogenesis.

Conclusions: Genetic variation in the transcription factor SOX5 is associated with COPD susceptibility. A mouse model suggests that the effect may be due, in part, to its effects on lung development and/or repair processes.

Rationale: Genome-wide association studies have shown significant associations between variants near hedgehog interacting protein HHIP, FAM13A, and cholinergic nicotinic acetylcholine receptor CHRNA3/5 with increased risk of chronic obstructive pulmonary disease (COPD) in smokers; however, the disease mechanisms behind these associations are not well understood.

Objectives: To identify the association between replicated loci and COPD-related phenotypes in well-characterized patient populations.

Methods: The relationship between these three loci and COPD-related phenotypes was assessed in the Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-point (ECLIPSE) cohort. The results were validated in the family-based International COPD Genetics Network (ICGN).

Measurements and Main Results: The CHRNA3/5 locus was significantly associated with pack-years of smoking (P = 0.002 and 3 × 10−4), emphysema assessed by a radiologist using high-resolution computed tomography (P = 2 × 10−4 and 4.8 × 10−5), and airflow obstruction (P = 0.004 and 1.8 × 10−5) in the ECLIPSE and ICGN populations, respectively. However, variants in the IREB2 gene were only significantly associated with FEV1. The HHIP locus was not associated with smoking intensity but was associated with FEV1/FVC (P = 1.9 × 10−4 and 0.004 in the ECLIPSE and ICGN populations). The HHIP locus was also associated with fat-free body mass (P = 0.007) and with both retrospectively (P = 0.015) and prospectively (P = 0.024) collected COPD exacerbations in the ECLIPSE cohort. Single-nucleotide polymorphisms in the FAM13A locus were associated with lung function.

Conclusions: The CHRNA3/5 locus was associated with increased smoking intensity and emphysema in individuals with COPD, whereas the HHIP and FAM13A loci were not associated with smoking intensity. The HHIP locus was associated with the systemic components of COPD and with the frequency of COPD exacerbations. FAM13A locus was associated with lung function.

This review proposes a critical reassessment (based entirely on published evidence) of the following seven common beliefs about chronic obstructive pulmonary disease (COPD): (1) COPD is one disease. (2) There is a valid definition for COPD. (The current definition includes cases of irreversible asthma and bronchiectasis, and occasionally, other obstructive lung conditions). (3) Irreversible asthma in smokers and COPD cannot be differentiated. (4) A “chronic bronchitis” form of COPD exists and is characterized by blue bloater status and normal carbon monoxide diffusion studies. (5) Phenotyping has no bearing on medication choice in COPD. (6) Computerized scoring of lung attenuation on CT scans can diagnose emphysema. (Emphysema scores overlap in irreversible asthma and COPD); however, qualitative visual changes may be useful for differentiation. (7) A definable entity called the overlap (of COPD and asthma) syndrome exists. Conflict over the abovementioned points denies patients proper phenotype-guided therapy and encourages a multidrug approach to COPD management. The recently coined term, overlap syndrome, invites a double-barreled therapy aimed at asthma and COPD, despite the absence of any agreement about how to define the syndrome and the lack of any related drug trials (in the area of inhaled corticosteroids). A diagnosis of COPD is associated with high morbidity and escalating costs, suggesting the need for a thorough new examination of the evidence.

Similar to other common chronic diseases, chronic obstructive pulmonary disease (COPD) is a heterogeneous disorder with multiple disease subtypes. Candidate gene studies have found genetic associations for COPD-related phenotypes that may be relevant for pharmacogenetics studies, including lung function decline and COPD exacerbations. However, few COPD pharmacogenetics studies have been completed. Most studies have focused on the role of variants in the β2-adrenergic receptor gene on bronchodilator response, but the findings have been inconclusive. Candidate gene studies highlight the concept that genes for COPD susceptibility may also be relevant in COPD pharmacogenetics. Currently, there are no clinical applications of pharmacogenetics to COPD therapy, but the use of pharmacogenetics to determine initial smoking cessation therapy may be closer to clinical application.

Observational epidemiologic studies of dietary antioxidant intake, serum antioxidant concentration, and lung outcomes suggest that lower levels of antioxidant defenses are associated with decreased lung function. Another approach to understanding the role of oxidant/antioxidant imbalance in risk of Chronic Obstructive Pulmonary Disease (COPD) is to investigate the role of genetic variation in antioxidant enzymes, and indeed family-based studies suggest a heritable component to lung disease. Many studies of the genes encoding antioxidant enzymes have considered COPD or COPD-related outcomes, and a systematic review is needed to summarise the evidence to date, and to provide insights for further research.

Genetic association studies of antioxidant enzymes and COPD/COPD-related traits, and comparative gene expression studies with disease or smoking as the exposure were systematically identified and reviewed. Antioxidant enzymes considered included enzymes involved in glutathione (GSH) metabolism, in the thioredoxin (TXN) system, superoxide dismutases (SOD), and catalase (CAT).

A total of 29 genetic association and 15 comparative gene expression studies met the inclusion criteria. The strongest and most consistent effects were in the genes GCL, GSTM1, GSTP1, and SOD3. This review also highlights the lack of studies for genes of interest, particularly GSR, GGT, and those related to TXN. There were limited opportunities to evaluate a gene’s contribution to disease risk through a synthesis of results from different study designs, as the majority of studies considered either association of sequence variants with disease or effect of disease on gene expression. Network-driven approaches that consider potential interaction between genes and amoung genes, smoke exposure, and antioxidant intake are needed to fully characterise the role of oxidant/antioxidant balance in pathogenesis.

Vitamin D deficiency is linked to accelerated decline in lung function, increased inflammation, and reduced immunity in chronic lung diseases. Epidemiological studies have suggested that vitamin D insufficiency is associated with low lung function in susceptible subjects who are exposed to higher levels of environmental agents (airborne particulates). Recent studies have highlighted the role of vitamin D and vitamin D receptor (VDR) in regulation of several genes that are involved in inflammation, immunity, cellular proliferation, differentiation, and apoptosis. Vitamin D has also been implicated in reversal of steroid resistance and airway remodeling, which are the hallmarks of chronic obstructive pulmonary disease (COPD) and severe asthma. VDR protein level is decreased in lungs of patients with COPD. VDR deficient mice develop an abnormal lung phenotype with characteristics of COPD, such as airspace enlargement and decline in lung function associated with increased lung inflammatory cellular influx, and immune-lymphoid aggregates formation. Dietary vitamin D may regulate epigenetic events, in particular on genes which are responsible for COPD susceptibility. Active metabolite of vitamin D, 1,25-dihydroxyvitamin D3 plays an essential role in cellular metabolism and differentiation via its nuclear receptor (VDR) that cooperates with several other chromatin modification enzymes (histone acetyltransferases and histone deacetylases), thereby mediating complex epigenetic events in vitamin D signaling and metabolism. This review provides an update on the current knowledge and understanding on vitamin D, and susceptibility of chronic lung diseases in relation to the possible role of epigenetics in its molecular action. Understanding the molecular epigenetic mechanism of vitamin D/VDR would provide rationale for dietary vitamin D-mediated intervention in prevention and management of chronic lung diseases linked with vitamin D deficiency.

Chronic obstructive pulmonary disease (COPD) and lung cancer are leading cause of death, and both are associated with cigarette smoke exposure. It has been shown that 50–70% of patients diagnosed with lung cancer suffer from COPD, and reduced lung function is an important event in lung cancer suggesting an association between COPD and lung cancer. However, a causal relationship between COPD and lung tumorigenesis is not yet fully understood. Recent studies have suggested a central role of chronic inflammation in pathogenesis of both the diseases. For example, immune dysfunction, abnormal activation of NF-κB, epithelial-to-mesenchymal transition, altered adhesion signaling pathways, and extracellular matrix degradation/altered signaling are the key underlying mechanisms in both COPD and lung cancer. These parameters along with other processes, such as chromatin modifications/epigenetic changes, angiogenesis, and autophagy/apoptosis are altered by cigarette smoke, are crucial in the development of COPD and lung cancer. Understanding the cellular and molecular mechanisms underlying these processes will provide novel avenues for halting the chronic inflammation in COPD and devising therapeutic strategies against lung cancer.

A genetic contribution to develop chronic obstructive pulmonary disease (COPD) is well established. However, the specific genes responsible for enhanced risk or host differences in susceptibility to smoke exposure remain poorly understood. The goal of this review is to provide a comprehensive literature overview on the genetics of COPD, highlight the most promising findings during the last few years, and ultimately provide an updated COPD gene list. Candidate gene studies on COPD and related phenotypes indexed in PubMed before January 5, 2012 are tabulated. An exhaustive list of publications for any given gene was looked for. This well-documented COPD candidate-gene list is expected to serve many purposes for future replication studies and meta-analyses as well as for reanalyzing collected genomic data in the field. In addition, this review summarizes recent genetic loci identified by genome-wide association studies on COPD, lung function, and related complications. Assembling resources, integrative genomic approaches, and large sample sizes of well-phenotyped subjects is part of the path forward to elucidate the genetic basis of this debilitating disease.

Video abstract

Several epidemiologic studies have found that smokers with chronic obstructive pulmonary disease (COPD), an inflammatory disease of the lung, have an increased risk of lung cancer compared to smokers without COPD. We have shown a causal role for COPD-like airway inflammation in lung cancer promotion in the CCSPCre/LSL–K-rasG12D mouse model (CC-LR). In contrast, existing epidemiologic data do not suggest any definite association between allergic airway inflammation and lung cancer. To test this, CC-LR mice were sensitized to ovalbumin (OVA) then challenged with an OVA aerosol weekly for eight weeks. This resulted in eosinophilic lung inflammation associated with increased levels of T helper 2 cytokines and mucous metaplasia of airway epithelium, similar to what is seen in asthma patients. However, this type of inflammation did not result in a significant difference in lung surface tumor number (49 ± 9 in OVA vs 52 ± 5 in control), in contrast to a 3.2-fold increase with COPD-like inflammation. Gene expression analysis of NTHi-treated lungs showed up-regulation of a different profile of inflammatory genes, including interleukin 6 (IL-6), compared to OVA-treated lungs. Therefore, to determine the causal role of cytokines that mediate COPD-like inflammation in lung carcinogenesis, we genetically ablated IL-6 in CC-LR mice. This not only inhibited intrinsic lung cancer development (1.7-fold), but also inhibited the promoting effect of extrinsic COPD-like airway inflammation (2.6-fold). We conclude that there is a clear specificity for the nature of inflammation in lung cancer promotion, and IL-6 has an essential role in lung cancer promotion.

Chronic obstructive pulmonary disease (COPD) is one of the leading causes of death throughout the world and is largely associated with cigarette smoking. Despite the appreciation of the central role of smoking in the development of COPD, only a relatively small number of smokers (15%–20%) develop COPD. Recent studies depicting familial aggregation suggest that some subjects may have a genetic predisposition to developing COPD. In this respect, a number of single nucleotide polymorphisms have been reported in association with different COPD features (subphenotypes), although much of this data remains controversial. Classical genetic studies (including twin and family studies) assume an “equal-environment” scenario, but as gene-environment interactions occur in COPD, this assumption needs revision. Thus, new integrated models are needed to examine the major environmental factors associated with COPD which include smoking as well as air pollution, and respiratory infections, and not only genetic predisposition. Revisiting this area, may help answer the question of what has more bearing in the pathogenesis of COPD—the environment or the genomic sequence of the affected subjects. It is anticipated that an improved understanding of this interaction will both enable improved identification of individuals susceptible to developing this disease, as well as improved future treatments for this disease.

Background

The relationship between inflammation, air obstruction and lung cancer is complex and there is still great uncertainty regarding their underlying pathophysiology. Our aim was to investigate the inflammation pathways that are implicated in both chronic obstructive pulmonary disease (COPD) and lung cancer.

Methods

A literature search was performed in PubMed to identify relative studies published until June 2011.

Results

The pathophysiology of both COPD and lung cancer includes dysregulation of the inflammation process, but the cascade of signaling events is not yet fully understood. Both lung cancer and COPD are associated with cigarette smoking that induces a chronic inflammatory state in the lung by generating reactive oxidant species. It is considered that shared inflammatory pathways involve genetic and epigenetic changes due to chronic tissue injury and abnormal tumor immunity in susceptible hosts. The proposed role of chronic inflammation is based on the 2-stage model of carcinogenesis. According to this model, genotoxic injury is crucial in tumorigenesis, followed by promotional events that result in clonal growth of modulated cells. Research has shown that chronic inflammation creates the necessary environment for the development of lung cancer, acting as a tumor promoter. This environment, in combination with cigarette smoke, induces the upregulation of mediators of the inflammatory response, such as cyclooxygenase-2. This leads to the production of inflammatory cytokines through lymphocytes, such as IL-1, IL-6, IL-8 and IL-10, as well as to the increased formation of chemotactic factors. Some of the latter mediators may suppress cell mediated immune response and promote angiogenesis. They also impact cell growth, resulting in the inhibition of apoptosis. Inflammatory factors promote oxidative stress, contribute to the generation of reactive oxygen, and cause oxidative DNA base modification. COX-2 also plays an important role in promoting epithelial-to-mesenchymal transition, present in both lung cancer and COPD. Thus, chronic inflammation plays a pathogenic role in lung cancer by inducing preneoplastic mutations and cellular damage.

Conclusions

Additional research is required to understand the cellular and molecular mechanisms that link COPD and lung cancer, in an effort to discover new methods of prevention and treatment.

Recently, several genome-wide association studies (GWAS) have identified many susceptible single nucleotide polymorphisms (SNPs) for chronic obstructive pulmonary disease (COPD) and lung cancer which are two closely related diseases. Among those SNPs, some of them are shared by both the diseases, reflecting there is possible genetic similarity between the diseases. Here we tested the hypothesis that whether those shared SNPs are common predictor for risks or prognosis of COPD and lung cancer. Two SNPs (rs6495309 and rs1051730) located in nicotinic acetylcholine receptor alpha 3 (CHRNA3) gene were genotyped in 1511 patients with COPD, 1559 lung cancer cases and 1677 controls in southern and eastern Chinese populations. We found that the rs6495309CC and rs6495309CT/CC variant genotypes were associated with increased risks of COPD (OR = 1.32, 95% C.I. = 1.14–1.54) and lung cancer (OR = 1.57; 95% CI = 1.31–1.87), respectively. The rs6495309CC genotype contributed to more rapid decline of annual Forced expiratory volume in one second (FEV1) in both COPD cases and controls (P<0.05), and it was associated with advanced stages of COPD (P = 0.033); the rs6495309CT/CC genotypes conferred a poor survival for lung cancer (HR = 1.41, 95%CI = 1.13–1.75). The luciferase assays further showed that nicotine and other tobacco chemicals had diverse effects on the luciferase activity of the rs6495309C or T alleles. However, none of these effects were found for another SNP, rs1051730G>A. The data show a statistical association and suggest biological plausibility that the rs6495309T>C polymorphism contributed to increased risks and poor prognosis of both COPD and lung cancer.