Genetics of COPD

doi:10.1378/chest.125.5.1929

Chest

Volume 125, Issue 5, May 2004, Pages 1929-1940

https://doi.org/10.1378/chest.125.5.1929 Get rights and content

COPD is a complex mix of signs and symptoms in patients with chronic bronchitis and emphysema, diseases that largely result from cigarette smoking. Not all smokers, however, acquire COPD, and COPD can develop in nonsmokers. In the United States, COPD is currently the fourth leading cause of death. Surprisingly, there are no effective drug therapies for COPD that are able to significantly alter disease progression, and little is known of the underlying molecular mechanisms that are responsible for its occurrence. Candidate gene-association studies and linkage analyses have been reported for COPD patients. This review describes the genetic predisposition of healthy subjects or relatives of COPD patients to acquire COPD. In addition, the genetic bases of COPD with rapid decline of FEV₁ are described, and the current genetic data that have been distilled from studies of COPD patients with a predominant emphysema phenotype, with chronic bronchitis phenotype, and with a response to bronchodilators are discussed.

Section snippets

Genetic Studies in COPD

The genetic bases of COPD have been investigated using association studies of candidate genes that can play a role in the pathogenesis of COPD. The limitations of this approach are that only known genes can be examined, patients and control subjects are difficult to match, and studies have small sample sizes or include patients of various ethnicities, which result in a lack of reproducibility across studies.

Some linkage or positional cloning studies also have been reported. In these studies,

Healthy Subjects at Risk and Relatives of COPD Patients

Healthy subjects have been studied to pinpoint the genetic determinants of airway function as well as the predisposing factors that may confer susceptibility to COPD. These studies have found that COPD, like asthma,¹⁷¹⁸ seems to be a multigenic disease (Table 1).

The genetic determinants of FEV₁, FVC, and the FEV₁/FVC ratio have been studied by linkage analysis in both healthy subjects and COPD patients. In healthy young adults, a 10-centimorgan (cM) genome-wide scan of 1,578 members in 330

Smokers Who Develop COPD

Only a fraction of smokers acquire COPD.²⁸²⁹ It appears that smokers who acquire COPD may have a different genotype than those lifelong smokers in whom lung function declines at a slower pace or not at all. This predisposition of some smokers to acquire COPD has been investigated by genetic epidemiology and candidate gene association studies (Table 2). In this regard, the prevalence of the PiZ alleles of the α₁AT gene in heavy smokers with COPD and in nonobstructed smokers appears to be

COPD With Predominant Emphysema Phenotype

Emphysema has been defined as a lung condition that is characterized by abnormal permanent enlargement of the distal airways accompanied by alveolar wall destruction with or without fibrosis. It has now become apparent that apoptosis of epithelial, endothelial, and other cells in the lung, together with excessive proteolysis and oxidative stress, contribute to the destruction of the lung.⁴²⁴³⁴⁴⁴⁵ As such, it is not surprising that many genes, other than α₁AT seem to be implicated in the

COPD With Predominant Bronchitic Phenotype

Chronic bronchitis is characterized by chronic cough and sputum production. There are few genetic studies that have addressed this particular phenotype (Table 4).

An autosomal 10-cM genome-wide scan of STR polymorphic markers was analyzed for linkage to COPD-related phenotypes in 585 members of 72 pedigrees ascertained through severe, early-onset COPD probands without severe α₁AT deficiency.⁵⁸ Multipoint nonparametric linkage analysis was performed for qualitative phenotypes, including moderate

COPD Phenotype With Response to Bronchodilators

Approximately half of COPD patients have a variable response to β₂-agonists or ipratropium from visit to visit, and this variability is unrelated to their smoking status, atopy, withdrawal of therapy with inhaled corticosteroids, or disease progression.⁴ The genotype of responders vs nonresponders may be different. However, both candidate gene association studies and linkage analysis studies in this phenotype are scarce (Table 5).

To identify the susceptibility loci for bronchodilator response

Conclusions

It is often stated that further knowledge of the genetics of COPD may lead to new treatments or to an increased ability to identify risk genotypes. However, current knowledge of the genetics of COPD is limited. Different and extreme COPD phenotypes are likely due to different gene mutations or polymorphisms, and these data are now emerging from candidate gene and linkage analysis studies. As we await more evidence, and bearing in mind that inconsistent results may be due to the phenotype

Glossary of Terms

Allele: one of the variant forms of a gene at a particular locus, or location, on a chromosome.

Apoptosis: programmed cell death, the body's normal method of disposing of damaged, unwanted, or unneeded cells.

Candidate gene: a gene, located in a chromosome region suspected of being involved in a disease, the protein product of which suggests that it could be the disease gene in question.

Centimorgan: a measure of genetic distance that tells how far apart two genes are. Generally, 1 cM equals about

ACKNOWLEDGMENT

I would like to thank June Baldwin for help with the preparation of this manuscript.

References (65)

DF Rogers
The airway goblet cell
Int J Biochem Cell Biol
(2003)
JA Nadel
Role of neutrophil elastase in hypersecretion during COPD exacerbations, and proposed therapies
Chest
(2000)
JM Drazen
Asthma and the human genome project: summary of the 45th Annual Thomas L. Petty Aspen Lung Conference
Chest
(2003)
TD Howard et al.
Mapping susceptibility genes for allergic diseases
Chest
(2003)
EK Silverman et al.
Genomewide linkage analysis of quantitative spirometric phenotypes in severe early-onset chronic obstructive pulmonary disease
Am J Hum Genet
(2002)
GE Silva et al.
A longitudinal study of {alpha}1-antitrypsin phenotypes and decline in FEV₁in a community population
Chest
(2003)
DM Mannino
COPD: epidemiology, prevalence, morbidity and mortality, and disease heterogeneity
Chest
(2002)
H Hirai et al.
Microsatellite polymorphism in heme oxygenase-1 gene promoter is associated with susceptibility to oxidant-induced apoptosis in lymphoblastoid cell lines
Blood
(2003)
J Lieberman et al.
Alpha 1-antitrypsin Pi-types in 965 COPD patients
Chest
(1986)
N Seersholm et al.
Intermediate alpha 1-antitrypsin deficiency PiSZ: a risk factor for pulmonary emphysema?
Respir Med
(1998)

W Poller et al.

A leucine-to-proline substitution causes a defective alpha 1-antichymotrypsin allele associated with familial obstructive lung disease

Genomics

(1993)

S Sakao et al.

Association of tumor necrosis factor-{alpha} gene promoter polymorphism with low attenuation areas on high-resolution CT in patients with COPD

Chest

(2002)

N Minematsu et al.

Genetic polymorphism in matrix metalloproteinase-9 and pulmonary emphysema

Biochem Biophys Res Commun

(2001)

CAD Smith et al.

Association between polymorphism in gene for microsomal epoxide hydrolase and susceptibility to emphysema

Lancet

(1997)

N Yamada et al.

Microsatellite polymorphism in the heme oxygenase-1 gene promoter is associated with susceptibility to emphysema

Am J Hum Genet

(2000)

LI Ho et al.

Polymorphisms of the {beta}2-adrenoceptor in COPD in Chinese subjects

Chest

(2001)

National Institutes of Health, National Heart, Lung, and Blood Institute

(2003)

Cited by (115)

Genotype is associated with smoking and other key health behaviors among individuals with alpha-1 antitrypsin deficiency-associated lung disease
2018, Respiratory Medicine
Citation Excerpt :
Alpha-1 antitrypsin deficiency (AATD) is a genetic condition that increases the risk of developing lung disease [1]. The emphysema subtype of chronic obstructive pulmonary disease (COPD) is the most common health problem caused by AATD [2,3]. Various environmental exposures influence the risk of developing lung disease, but the primary factors that influence this risk are cigarette smoking and the severity of AATD [4–6].
To examine the association of genotype with smoking and other key health behaviors among individuals with alpha-1 antitrypsin deficiency (AATD) associated lung disease.
Self-reported data were analyzed from 3506 individuals with AATD-associated lung disease. All data were collected upon enrollment in a disease management program designed for individuals who have been prescribed augmentation therapy. Multivariate logistic regression was utilized to examine the extent to which genotype was associated with smoking and other key health behaviors (i.e., getting a pneumonia vaccine, getting a flu vaccine, exercising, and maintaining a healthy weight). We hypothesized that MZs and SZs are more likely than ZZs to be current smokers, and that genotype is associated with additional health behaviors.
MZs and SZs had higher odds of being a current smoker than ZZs (MZ versus ZZ OR = 2.73, p < .001; SZ versus ZZ OR = 4.34, p < .001). For every additional health behavior examined, MZs had higher odds of unhealthy behavior than ZZs (ORs ranged from 1.35 to 1.98, p < .05). SZs had higher odds of unhealthy behavior than ZZs with regard to lack of exercise (OR = 1.52, p = .003) and failure to maintain a healthy weight (underweight OR = 1.93, p = .028; overweight OR = 1.43, p = .015).
Among individuals who have been prescribed augmentation therapy for lung disease due to AATD, genotype is associated with smoking and additional health behaviors that are central to managing lung disease.
Beta<inf>2</inf>-adrenergic receptor gene haplotypes and bronchodilator response in Egyptian patients with chronic obstructive pulmonary disease
2017, Advances in Medical Sciences
Chronic obstructive pulmonary disease (COPD) is a multi-factorial disorder caused by environmental determinants and genetic risk factors. Understanding the genetic predisposition of COPD is essential to develop personalized treatment regimens. Beta₂-adrenergic receptor (ADRB2) gene polymorphisms have been implicated in the pathogenesis of obstructive pulmonary diseases. This study was conducted to assess the genetic association between Arg16Gly and Gln27Glu polymorphisms and COPD in the Egyptian patients, and to analyze their impact on the clinical outcome and therapeutic response.
The study population included 115 participants (61 COPD patients and 54 healthy controls) were genotyped for the Arg16Gly (rs1042713) and Gln27Glu (rs1042714) polymorphisms. Pulmonary function test was done and repeated in patients after salbutamol inhalation.
The Gly₁₆ and Gln₂₇ alleles represented 57% and 70% of the whole study population, and only 3 haplotypes were detected; Arg₁₆/Gln₂₇, Gly₁₆/Gln₂₇, and Gly₁₆/Glu₂₇. Genotypes and haplotypes homozygous for Arg₁₆ and Gln₂₇ were more likely to develop COPD (p < 0.05). However, individuals carrying Glu₂₇ allele conferred protection against COPD development (p = 0.002). Furthermore, Arg₁₆ genotypes and haplotypes were significantly associated with higher grades of dyspnea, more COPD symptoms and frequent exacerbations. In contrast, patients carrying Glu₂₇ allele had better bronchial airway responsiveness to β₂-agonists.
Our findings suggested that the ADRB2 gene polymorphisms may have vital role in COPD risk, severity, and bronchodilator response among Egyptian population. Larger epidemiological studies are needed for results validation.
Genomic mechanisms of transformation from chronic obstructive pulmonary disease to lung cancer
2017, Seminars in Cancer Biology
Citation Excerpt :
It was estimated that COPD incidence is increasing at the rate of is about 1–2 percentage and the population of COPD may be about 85 million in 2030, of which approximately 1% develop lung cancer every year [4]. COPD and lung cancer are major respiratory diseases with a large amount of genetic variations and a high sensitivity to environmental risk factors [7–11]. The association between COPD and lung cancer was proposed by the finding that a considerable proportion of lung cancer patients have a history of COPD [12] and that COPD patients had four to six fold higher risk of developing lung cancer, as compared to smokers alone [13].
Genetic variations in COPD and lung cancer may be one of the molecular mechanisms responsible for COPD-lung cancer transformation. The present review highlights main genetic variations co-existed in COPD and lung cancer and integrates the varied genes into four molecular mechanisms, e.g. activated cell proliferation pathway, tumor suppressor and DNA repair gene dysfunction, chronic inflammatory microenvironment, and impaired immune response, by which COPD epithelial cells may be transformed into tumorigenic status. We call special attention to further investigate the transformation from COPD to lung cancer and understand the exact molecular mechanisms, to prevent and reduce the increased incidence of COPD and lung cancer. We call direct evidence to show the existence of COPD-lung cancer transformation, since current evidence to support the transformation from COPD to lung cancer is the co-existence of selected genes and proteins in both. We should furthermore explore and understand the homogeneity and heterogeneity of gene mutation, epigenetics, sequencing, and function between COPD and lung cancer. The defining and understanding of COPD-lung cancer transformation will provide new diagnostic and therapeutic biomarkers as a new milestone to prevent and treat lung cancer.
Cigarette smoke-induced hypermethylation of the GCLC gene is associated with COPD
2016, Chest
Cigarette smoking is a major environmental contributor to COPD, but understanding its epigenetic regulation of oxidative genes involved in the pathogenesis of COPD remains elusive.
We analyzed DNA methylation on glutamate-cysteine ligase catalytic subunit (GCLC), glutathione S-transferase M1 (GSTM1), glutathione S-transferase P1 (GSTP1), and superoxide dismutase 3 (SOD3) promoters in clinical samples from patients with COPD (current-smoker [CS-COPD]; ex-smoker [ES-COPD]) and subjects with normal pulmonary function (current-smoker [CS-NS]; ex-smoker [ES-NS]; never-smoker [NC]). Expression of GCLC messenger RNA (mRNA) and glutathione (GSH) synthesis in these clinical samples and human bronchial epithelial (BEAS-2B) cells stimulated by cigarette-smoke extract (CSE) was evaluated. GCLC mRNA and protein levels were measured to determine effects of demethylation and deacetylation agents on CSE-treated BEAS-2B cells.
The DNA methylation level of the GCLC promoter was significantly increased in CS-COPD, CS-NS, and ES-COPD groups compared with ES-NS and NC groups. However, there were no significant differences in DNA methylation values of GSTM1, GSTP1, and SOD3 promoters among these groups. Expression of GCLC mRNA was downregulated in the lungs, and GSH levels decreased in plasma as a consequence of hypermethylation of the GCLC promoter. Similarly, CSE-treated BEAS-2B cells had hypermethylation of the GCLC gene, mRNA downregulation, and a decreased intracellular GSH level. GCLC expression in CSE-treated BEAS-2B cells was restored by the methylation inhibitor, 5-aza-2ʹ-deoxycytidine, but not by the deacetylation agent, trichostatin A.
Cigarette smoke-induced hypermethylation of the GCLC promoter is related to the initiation and progression of COPD. Our finding may provide a new strategy for COPD intervention by developing demethylation agents targeting GCLC hypermethylation.
Association between glutathione S-transferase P1 Ile (105) Val gene polymorphism and chronic obstructive pulmonary disease: A meta-analysis based on seventeen case-control studies
2015, Meta Gene
Citation Excerpt :
However, only 10–15% of smokers develop clinically significant COPD (Mannino et al., 2002; Salvi, 2014). Many COPD patients have a family history and several studies have showed that the individual's risk differences to tobacco smoke injury may be related to genetic factors and the genetic factors may also play an important role in the pathogenesis of COPD (Hoidal, 2001; Molfino, 2004). Therefore, it is widely believed that COPD results from an interaction between genetic factors and environmental exposures.
Previous studies have shown that glutathione S-transferase P1 (GSTP1) was associated with chronic obstructive pulmonary disease (COPD). However, the association between GSTP1 Ile (105) Val gene polymorphism and COPD remains controversial. To drive a more precise estimation, we performed a meta-analysis based on published case–control studies.
An electronic search of PubMed, EMBASE, Cochrane library, Web of Science and China Knowledge Resource Integrated (CNKI) Database for papers on GSTP1 Ile (105) Val gene polymorphism and COPD risk was performed. The pooled odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of association in the homozygote model, heterozygote model, dominant model, recessive model and an additive mode. Statistical heterogeneity, test of publication bias and sensitivity analysis was performed. The software STATA (Version 13.0) was used data analysis.
Overall, seventeen studies with 1892 cases and 2012 controls were included in this meta-analysis. The GSTP1 Ile (105) Val polymorphism showed pooled odds ratios for the homozygote comparison (OR = 1.501, 95%CI [0.862, 2.614]), heterozygote comparison (OR = 0.924, 95%CI [0.733, 1.165]), dominant model (OR = 1.003, 95%CI [0.756, 1.331]), recessive model (OR = 1.510, 95%CI [0.934, 2.439]), and an additive model (OR = 1.072, 95%CI [0.822, 1.398]).
In conclusion, the current meta-analysis, based on the most updated information, showed no significant association between GSTP1 Ile (105) Val gene polymorphism and COPD risk in any genetic models. The results of subgroup analysis also showed no significant association between GSTP1 Ile (105) Val gene polymorphism and COPD risk in Asian population and Caucasian population. Further studies involving large populations and careful control with age, sex, ethnicity, and cigarette smoking are greatly needed.
Association of Egr-1 and autophagy-related gene polymorphism in men with chronic obstructive pulmonary disease
2015, Journal of the Formosan Medical Association
Citation Excerpt :
Inconsistent results for the genetic predisposition of smokers to acquired COPD and genetics bases of COPD severity with rapid decline of FEV1 was also found in the matrix metalloproteinase; matrix metalloproteinase 9 polymorphisms are associated with the development of smoking-induced pulmonary emphysema, but not associated with a rapid decline of lung function. This result may be due to COPD susceptibility and progressive airflow limitations are different clinical phenotypes associated with different genes.2 Another possible reason was that spirometry is not a suitable severity assessment tool in the present study.
: Autophagy is important in cellular homeostasis and control of inflammatory immune response. Increased autophagy has recently been associated with increased cell death and chronic obstructive pulmonary disease (COPD) pathogenesis. Two autophagy regulator genes have been identified: Egr-1 (early growth response), associated with different phenotype expressions in asthma; and, Atg16L1 (autophagy related 16-like 1), a candidate gene responsible for susceptibility to chronic inflammatory diseases. We will explore the role of the Egr-1 and Atg16L1 gene polymorphisms in COPD.
The genotypes of 151 male smoking patients with COPD and 100 male smoking controls were evaluated by polymerase chain reaction followed by restriction fragment length polymorphism analysis of the Egr-1 (–4071 A → G) rs7729723 and Atg16L-1 (T300A) rs2241880 variants.
The G allele of the Egr-1 gene polymorphism was associated with an increased risk of developing COPD [odds ratio (OR), 2.05; 95% confidence interval (CI), 1.15–3.72], and participants with the G allele polymorphism (GG and GA genotypes) had a 2.56-fold higher risk (OR, 2.56; 95% CI, 1.31–5.16) of having COPD than those homozygous for the A allele [35.8% (54/151) vs. 24.0% (24/100); p = 0.007]. Participants with the A allele of the Atg16L1 gene polymorphism (AA and AG genotypes) had a 3.34-fold higher risk (OR, 3.34; 95% CI, 1.32–8.97) of having COPD than those homozygous for the G allele [93.4% (141/151) vs. 81.0% (81/100); p = 0.013].
The Egr-1 and Atg16L1 genes' polymorphisms were significant risk factors for susceptibility to COPD. These results demonstrate that autophagy regulator genetic mutations are associated with COPD in male smokers.

View all citing articles on Scopus

View full text

Chest

Impact of Basic Research on Tomorrow's MedicineGenetics of COPD

Section snippets

Genetic Studies in COPD

Healthy Subjects at Risk and Relatives of COPD Patients

Smokers Who Develop COPD

COPD With Predominant Emphysema Phenotype

COPD With Predominant Bronchitic Phenotype

COPD Phenotype With Response to Bronchodilators

Conclusions

Glossary of Terms

ACKNOWLEDGMENT

Int J Biochem Cell Biol

Chest

Chest

Chest

Am J Hum Genet

Chest

Chest

Blood

Chest

Respir Med

Genomics

Chest

Biochem Biophys Res Commun

Lancet

Am J Hum Genet

Chest

Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: NHLBI/WHO Workshop

Canadian Thoracic Society recommendations for management of chronic obstructive pulmonary disease-2003

Can Respir J

Prednisolone response in patients with chronic obstructive pulmonary disease: results from the ISOLDE study

Thorax

Bronchodilator reversibility testing in chronic obstructive pulmonary disease

Thorax

New concepts in chronic obstructive pulmonary disease

Annu Rev Med

Oxidative stress, chromatin remodeling and gene transcription in inflammation and chronic lung diseases

J Biochem Mol Biol

Pulmonary hypertension in chronic obstructive pulmonary disease

Eur Respir J

Remodeling in response to infection and injury: airway inflammation and hypersecretion of mucus in smoking subjects with chronic obstructive pulmonary disease

Am J Respir Crit Care Med

Morphologic and morphometric effects of prolonged cigarette smoking on the small airways

Am Rev Respir Dis

Rationale of airway clearance

Eur Respir J

Bacterial adhesion to oropharyngeal and bronchial epithelial cells in smokers with chronic bronchitis and in healthy nonsmokers

Eur Respir J

4-hydroxy-2-nonenal, a specific lipid peroxidation product, is elevated in lungs of patients with chronic obstructive pulmonary disease

Am J Respir Crit Care Med

Disruption of the klotho gene causes pulmonary emphysema in mice: defect in maintenance of pulmonary integrity during postnatal life

Am J Respir Cell Mol Biol

Oxidative stress and apoptosis interact and cause emphysema due to vascular endothelial growth factor receptor blockade

Am J Respir Cell Mol Biol

Genetic loci influencing lung function: a genome-wide scan in the Framingham study

Am J Respir Crit Care Med

A genome-wide scan of pulmonary function measures in the National Heart, Lung, and Blood Institute Family Heart Study

Am J Respir Crit Care Med

Impact of Basic Research on Tomorrow's Medicine
Genetics of COPD