Home | About us | Editorial Board | Search | Ahead of print | Current Issue | Archives | Instructions | Online submissionContact Us   |  Subscribe   |  Advertise   |  Login  Page layout
Wide layoutNarrow layoutFull screen layout
Lung India Official publication of Indian Chest Society  
  Users Online: 2827   Home Print this page  Email this page Small font size Default font size Increase font size

Year : 2006  |  Volume : 23  |  Issue : 1  |  Page : 15-19 Table of Contents   

COPD etiopathogenesis: Interplay of environmental and genetic factors

Emeritns Professor and Director, M. R. Medical College, Gulbarga, Karnataka., India

Correspondence Address:
P S Shankar
Emeritns Professor and Director, M. R. Medical College, Gulbarga, Karnataka.
Login to access the Email id

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0970-2113.44425

Rights and Permissions

How to cite this article:
Shankar P S. COPD etiopathogenesis: Interplay of environmental and genetic factors. Lung India 2006;23:15-9

How to cite this URL:
Shankar P S. COPD etiopathogenesis: Interplay of environmental and genetic factors. Lung India [serial online] 2006 [cited 2020 Feb 20];23:15-9. Available from: http://www.lungindia.com/text.asp?2006/23/1/15/44425

   Introduction Top

Chronic obstructive pulmonary disease (COPD) is a syndrome of progressive airflow limitation caused by chronic inflammation of the airways and lung parenchyma [1] . COPD is more common in men than women and it progresses with age and its natural history spans 20 to 40 years,

Cigarette Smoking

Cigarette smoking forms the single most important risk factor for development of COPD. Exposure to smoke from biomass and solid fuel fires contributes to the development of COPD in some individuals in developing countries. However it is intriguing why only 10 to 20 percent of chronic heavy smokers develop clinically significant COPD. There is an individual susceptibility to smoking. The studies have established a relationship between smoking history and decline in pulmonary function [2] . There is an accelerated decline in the forced expiratory volume in one second (FEV 1 ) from the normal rate in adults over 30 years of age of approximately 30 ml per year to nearly 60 ml per year [3] . The pack years and duration of smoking are able to account for nearly 15 per cent of the variation in FEV 1 levels.

Thus it is logical that other factors must be playing a role in the development of COPD. These factors may be environmental or genetic.

Environmental Factors

The environmental factors are;

  1. childhood viral respiratory infections
  2. latent adenovirus infections
  3. indoor air pollution
  4. occupational pollution from dusts and fumes

Genetic factors

Many epidemiologic studies have shown that there is a genetic basis to COPD. The genetic factors influence susceptibility to the ill effects of cigarette smoking leading to the development of COPD [4] . COPD is known to cluster in families, implying the genetic susceptibility to the disease. These individuals share a similar environment. The incidence of COPD is high in the relatives of cases compared with the relatives of controls. The incidence of COPD is 4.7 times higher among the siblings of smokers compared to those of matched controls.

Twin studies have enabled to assess the relative contributions of genes and environment to a trait in monozygotic (MZ) and dizygotic (DZ) twins. The variability of a trait due to genetic factors is called the heritability of that trait. Objectively, the variability can be demonstrated by estimating FEV 1 . The variability in FEV 1 is likely to be due to the differences in exposure to environmental factors in genetic background. The studies of pulmonary functions in the families have shown that they have a significant genetic component. There are many genes, each of which has a small but significant effect in bringing about the alteration. In the background of this, COPD is considered as a complex genetic disease having multiple susceptibility genes [5] .

Many lines of investigations such as linkage analysis, association studies, animal models, genome screening and mRNA differential display- have been followed to identify the genes that may influence the development or severity of COPD [6] .

Linkage analysis: Linkage analysis is a method to identify susceptibility genes for disease. It compares the inheritance of the disease with the inheritance of genetic markers in families with multiple affected members. Unfortunately, this type of analysis is difficult to use in most families with COPD as the symptoms develop only after prolonged exposure to cigarette smoke.

   Pathogenesis of COPD Top

COPD is characterized by a fall in expiratory flow and lung hyperinflation. These changes are due to loss of lung elasticity and inflammatory narrowing of the small airways of the lung. A number of genes in conjunction with environmental factors, are likely to influence the development of airway inflammation and parenchymal destruction, in other words the susceptibility to COPD.

At present, most of the genes that contribute to the genetic component to COPD remain undetermined. The genes that are implicated in the pathogenesis of COPD are devided into 4 categories based on their functions:

  1. antiproteolysis
  2. xenobiotic metabolism of the toxic substances in the cigarette smoke
  3. inflammatory response to cigarette smoke, and
  4. mucociliary clearance in the lung

There are also other genes that have an indirect influence on the pathogenesis of COPD. They are likely to modify the disease phenotype.

  1. Degree of addiction to nicotine. This has significant influence on the beginning of smoking, number of cigarette smoked and the ability to quit smoking.
  2. Ventilatory response to hypercapnia and hypoxia

1. Antiproteolysis

Imbalances in relative amounts of proteases and antiproteases are thought to play a major role in the pathogenesis of COPD especially emphysema. Deficiencies or abnormalities in antiproteases could lead to enhaneced lung parenchymal destruction. Among the genes, alpha-1 antitrypsin deficiency has proved an important risk factor for COPD.

Alpha-1 antitrypsin (AAT) is a glycoprotein, capable of inhibiting a variety of serine proteinases. Its gene is located on human chromsome 14q31-32.3. It is found in serum and it circulates in a concentration of 120-200 mg/dl. AAT is synthesized predominantly by hepatocytes. Mononuclear phagocytes and intestinal and pulmonary epithelial cells also possess the capability to synthesize AAT.

There can be severe deficiency of AAT in serum and in tissues including lungs. It occurs due to inheritance of two protease inhibitor deficiency alleles from the AAT gene located on chromosome segment 14q 31-32.3 [7] . The deficiency allele is protease inhibitor (Pi) Z. Nearly 85 percent of the AAT synthesized is not released into the circulation and it is blocked in the terminal secretory pathway of the hepatocytes and gets accumulated in hepatocyte cytoplasm and large intracellular inclusions. It results in markedly low concentrations of AAT protein in the serum when it is in homozygous form (PiZZ). In such a situation, the level of AAT is usually less than 50mg/dl 8 . PiZZ is inherited as an autosomal codominant gene.

There are many genetic variants of AAT, which have been given designation alphabetically depending on their mobility in an electrophoretic field at alkaline pH. Earlier letters of the alphabet are given to rapidly migrating variants, and the latter letters to those variants that migrate slowly. Z variant is the slowest among all. Phenotype PiMM that is predominant in Caucasians, exhibits medium mobility and normal plasma levels. The other phenotypes that are associated with AAT deficiency are PiMZ, PiMS, PiSS and PiSZ. The name of AAT has been derived from its capability to inhibit trypsin. However, the major action is to inhibit neutrophil elastase (NE) responsible for degradation of elastin, basement membrane and other components of matrix [9] .

One of the important manifestations of AAT deficiency is COPD. Many risk factors play a role in the development of COPD in persons having PiZZ phenotype. AAT deficiency can cause emphysema in non-smokers but this risk is increased dramatically in patients with AAT who smoke. Smoking forms the most important risk factor for the development of emphysema. It has been observed that the annual decline of FEV 1 in smokers is about 70 ml [10] .Environmental exposure to gases, fumes and dusts has a deleterious effect on the lung function. Male sex, and siblings of index cases are other risk factors.

Emphysema develops as a result of a protease­ antiprotease imbalance. The imbalance is noted between the anti-elastase defenses of the lung and the relatively increased action of neutrophil elastase. The result is degradation of elastin of the gas exchanging regions of the lung. AAT is the major anti-elastase defense. Its absence results in destruction of the architecture of the lung leading to emphysema.

AAT gets inactivated, by the action of oxidants found in tobacco smoke. An increased number of neutrophils are recruited into the alveoli by cigarette smoke and it further aggravates the concentration of NE. Alveolar macrophages and neutrophils release a number of metalloproteinases that are capable of degrading the components of extracellular matrix [11] .

There is panacinar emphysema exhibiting destruction of all components of the acinus more or less uniformly. There is destruction of the walls of alveolar ducts and alveoli. The distinction between alveolar ducts and alveoli is lost [12] . There is total disorganization of the acinar architecture to result in large airspaces of irregular size and shape that compress the respiratory bronchioles during expiration. Alveoli of normal architecture are not present. The condition begins at the bases of the lung affecting more frequently, the lower lobes of the lung.

2. Xenobiotic metabolizing enzymes

Cigarette smoke contains many toxic and highly reactive compounds that can cause injury to the tissues and inflammation. Any change in the enzyme systems designed to detoxify reactive substances may contribute to an increased risk of development of COPD in some smokers.

a) Microsomal epoxide hydrolase: Microsomal epoxide hydrolase (mEH) is a xenobiotic metabolizing enzyme that converts reactive epoxides into more soluble dihydrodiol derivatives that are easily eliminated from the body. mEH is expressed in many different cell types including hepatocytes and bronchial epithelial cells. Thus mEH plays an important role in the metabolism of different highly reactive compounds found in cigarette smoke.

There is significant increase in homozygosity for the slow-activity mEH allele in patients with COPD [13] . Low levels of mEH make the lung vulnerble to damage by epoxides.

b) Gutathione S-transferases : The enzymes, glutathione S-transferases (GSTs) play an important role in detoxifying different aromatic hydrocarbons found in cigarette smoke. They conjugate electrophilic substrates with glutathione, and facilitate further metabolism and elimination.

GST-M1 is expressed in the bronchiolar epithelium, alveolar macrophages, and type-1 and type-2 pneumocytes [14] .Homozygous deficiency for GST-M1 results in emphysema and severe chronic bronchitis in heavy smokers [15] .

c) Cytochrome P4501A1 : Cytochrome (CYP1A1) participates in the metabolism of xenobiotic compounds and enable their excretion. CYP1A1 is found throughout the lung. A mutation in CYP1A1 results in its increased activity. A high-activity allele is associated with susceptibility to centriacinar emphysema in patients having lung cancer [16] .

3. Inflammatory mediators

Inflammatory mediators play a very important role in the pathogenesis of COPD. Genetic polymorphisms may either augment inflammation or impair anti-­inflammatory pathways and contribute to individual variability in their susceptibility to cigarette smoke.

a) Vitamin D binding protein : Vitamin D binding protein (VDBP) is a potential inflammatory mediator. It increases the chemotactic activity of C5a for neutrophils and it can act as a macrophage-activating factor (MAF) [17] . Three protein isoforms 1F and 2-are formed and there is substitution in exon 11 of the gene. It has been shown that those who have one or two copies of the 2 alleles are protected against COPD [18] . Prevalence of 1F genotype increases the risk for development of COPD [19] .

b) Tumor Necrosis Factor-alpha: The proinflammatory cytokines, tumor necrosis factor (TNF)-alpha and beta may play an important role in the pathogenesis of COPD. These cytokines cause release of neutrophils from the bone marrow and activate them. There are several polymorphisms in TNF­alpha and TNF-beta genes. The TNF-alpha­308A allele has shown an increased occurrence of COPD in patients having chronic bronchitis and impaired lung function [20] .

4. Mucociliary clearance

The clearance of particulate matter from the lungs varies form individual to individual. The genetic factors may affect an individual's mucociliary clearance rate.

Cystic fibrosis transmembrane regulator: Cystic fibrosis transmembrane regulator (CFTR) forms a chloride channel at the apical surface of airway epithelial cells and is actively concerned in the control or airway secretions. Mutation in CFTR gene is responsible for cystic fibrosis (CF). Cystic fibrosis is an autosomal recessive genetic disease. Its pathophysiologic abnormality is characterized by a defect in electrolyte transport in the airway epithelium. There is a decrease in secretion of chloride into the airway lumen and an increase in reabsorption of sodium from the airway lumen, leading to a decrease in water content and an increase in viscosity of airway secretions [21] . It is responsible for thick and poorly cleared inspissated airway secretions, impaired mucociliary clearance, chronic bacterial infections, bronchiectasis, and progressive respiratory failure.

Genetics of smoking and nicotine addiction

Genetic factors influence smoking behaviour. The studies in adolescent twin pairs has shown the likelihood of smoking attributable to genetic factors ranging between 31% and 84% [22] . The persistence of smoking results in COPD and it has a heritability of 53% that is independent of genetic factors for initiation [23] .

Cytochrome P450 A6: The enzyme, Cytochrome P450 A6 (CYP2A6) is responsible for the metabolism of nicotine to cotinine. Substitution of an amino acid in the CYP2A6 gene results in an enzyme with decreased activity [24] . Individuals with deficiency allele are less likely to be smokers and those who are smokers smoke less number of cigarettes [25] . This observation has not been conclusively proved.

Ventilatory response to hypoxia and hypercapnia

Two broad categories of chronic air flow limitation as chronic bronchitis and emphysema are noted. Bronchitis exhibits marked involvement of airways. The patient shows hypoventilation and retains carbon dioxide. Patients with emphysema exhibiting destruction of lung hyperventilate to keep the level of PaCO 2 down until late in the course of the disease when airflow is severely obstructed. During the course of the disease, though the patients can progress in one or the other direction, many fall in the intermediate group between these two polar types of disease.

There is great variability in responses to hypoxia and hypercapnia among individuals [26] . This variability may contribute to the different categories of COPD as 'blue bloater' and 'pink puffer' types. These phenotypes are extreme examples of the disorder. However, most patients exhibit features of both categories. Those who exhibit minimal ventilatory response to hypoxia and hypercapnia become blue bloaters and those with a large ventilatory response turn out to be pink puffers. Though no specific gene has been implicated for this variation, there must be some genetic component for the individual response to hypoxia and possibly hypercapnia.

   Conclusion Top

There is need to establish that genetic factors play an important role in occurrence of COPD. It is only possible by replication of the association in different populations. Each population exhibits different genetic risk factors. They may interact with each other and with environmental risk factors that may obscure the effect of the gene on the phenotype.

Alpha-1 antitrypsin, Glutathione S­transferases, Vitamin D binding protein and cystic fibrosis transmembrane regulator genes have been shown to be important genetic factors playing a role in the pathogenesis of COPD in many populations. Smoking is the most important risk factor in the development of COPD. The inclination to smoke cigarettes and the likelihood of quitting smoking are influenced by genetic factors.

   References Top

1.Barnes PJ. Chronic obstructive pulmonary disease. N Engl J Med 2000; 343: 269-80.  Back to cited text no. 1  [PUBMED]  [FULLTEXT]
2.Fletcher C, Peto R. The natural history of chronic airflow obstruction. Br Med J. 1977; 1: 1645-8.  Back to cited text no. 2    
3.Anthonisen NR, Connett JE, Murray RP. Smoking and lung function of Lung Health study participants after 11 years.Am J Respir Crit Care Med 2000; 166: 675-9.  Back to cited text no. 3    
4.Tager IB, Rosner B, TIshler PV et al. Household aggregation of pulmonary disease. Clin Chest Med 2000; 21: 633-643.  Back to cited text no. 4    
5.Standford AJ, Pare PD. Genetic risk factors for chronic obstructive pulmonary disease. Clin Chest Med 2000; 21:633-643.  Back to cited text no. 5    
6.Barnes PJ. Molecular genetics of chronic obstructive pulmonary disease. Thorax 1999; 54:245.  Back to cited text no. 6  [PUBMED]  [FULLTEXT]
7.Cox DW, Billingsley GD, Mansfield T. DNA restriction site polymorphism associated with the alpha-1 antitrypsin gene. Am J Hum Genet 1987; 41:891-901.  Back to cited text no. 7  [PUBMED]  [FULLTEXT]
8.Tobin MJ, Cook PH, Hutchison DCS. Alpha-1 antitrypsin deficiency: the clinical and physiological features of pulmonary emphysema in subjects homozygous for Pi type Z. Br J Dis Chest 1983; 77: 14-27.  Back to cited text no. 8    
9.Stockley RA. The pathogenesis of chronic obstructive lung disease: implications for therapy. A J Med 1995; 88: 141­-146.  Back to cited text no. 9    
10.Pitulainen E, Eriksson S. Decline in FEV 1 related to smoking status in individuals with severe alpha-1 antitrypsin deficiency (PiZZ). Eur Respir J 1999;13: 247-251.  Back to cited text no. 10    
11.Hantamaki RD, Kobayashi DK, Senior RM, Shapiro SD. Requirement for macrophage elastase for cigarette smoke induced emphysema in mice. Science 1997; 277: 2002-2004.  Back to cited text no. 11    
12.Thurlbeck WM, Dunnill MS, Hartung E, et al. A comparison of three methods of measuring elastase for cigarette smoke induced emphysema in mice. Science 1997; 277: 2002-­2004.  Back to cited text no. 12    
13.Smith CA, Harrison DJ. Association betweeen polymorphism in gene for microsomal epoxide hydrolase and susceptibility to emphysema. Lancet 1997;350:630.  Back to cited text no. 13  [PUBMED]  [FULLTEXT]
14.Cantlay AM, Smith CA, Wallace WA, et al. Heterogeneous expression and polymorphic genotype of glutathione S­transferase in human lung. Thorax 1994;49: 1010.  Back to cited text no. 14  [PUBMED]  [FULLTEXT]
15.Baranova H, Perriot J, Albuisson E, et al. Peculiarities of the GSTM1 0/0 genotype in French heavy smokers with various types of chronic bronchitis. Hum Genet 1997; 99: 802.  Back to cited text no. 15    
16.Cantlay AM, Lamb D, Gillooly M, et al. Association between the CPY1A1 gene polymorphism and susceptibility to emphysema and lung cancer. J Clin Pathol Mol Pathol 1995; 48:M210.  Back to cited text no. 16    
17.Yamamoto N, Homma S, Vitamin D-binding protein (group­specific component) is a precursor for the macrophage­activating signal factor from lysophosphatidylcholine-treated lymphocytes. Proc Natl Acad Sci USA. 1991; 88: 8539.  Back to cited text no. 17    
18.Schellenberg D, Pare PD, Weir TD, et al. Vitamin D­binding protein variants and the risk of COPD. Am J Respir Crit Care Med 1998; 157:957.  Back to cited text no. 18    
19.Home SL, Cockcroft DW, Dosman JA. Possible protective effect against chronic obstructive airways disease by the GC 2 allele. Hum Hered 1990; 40:173.  Back to cited text no. 19    
20.Huang SL, Su CH, Chang SC. Tumor necrosis factor-alpha gene polymorphism in chronic bronchitis. Am J Respir Crit Care Med 1997; 156: 1436.  Back to cited text no. 20  [PUBMED]  [FULLTEXT]
21.Davis PB. Cystic fibrosis; from bench to bed side. N Engl J Med 1991; 325: 575-577.  Back to cited text no. 21  [PUBMED]  
22.Boomsma DI, Koopmans JR, Van Doornen LJ, et al. Genetic and social influences on starting to smoke: A study of Dutch abolescent twins and their parents. Addiction 1994;89:219.  Back to cited text no. 22  [PUBMED]  [FULLTEXT]
23.Heath AC, Martin NG, Genetic models for the natural history of smoking: Evidence for a genetic influence on smoking persistence. Addict Behav. 1993; 18:19.  Back to cited text no. 23    
24.Fernandez-Salguem P, Hoffman SM, Cholerton S, et al. A genetic polymorphism in coumarin 7-hydroxylation: Sequence of the human CYP2A genes and identification of variant CYP2A6 alleles. Am J Hum Genet 1995; 57:651.  Back to cited text no. 24    
25.Pianezza Ml, Sellers EM, Tyndale RF. Nicotine metabolism defect reduces smoking. Nature 1998; 393: 750.  Back to cited text no. 25  [PUBMED]  [FULLTEXT]
26.Hirshman CA, McCullough RE, Weil JV. Normal values for hypoxic and hypercapnic ventilatory drives in man. J Appl Physiol 1975; 38:1095.  Back to cited text no. 26  [PUBMED]  [FULLTEXT]


    Access Statistics
    Email Alert *
    Add to My List *
* Registration required (free)  

  In this article
    Pathogenesis of COPD

 Article Access Statistics
    PDF Downloaded427    
    Comments [Add]    

Recommend this journal