Genetic risk factors for chronic obstructive pulmonary disease

Abstract

Cigarette smoking is the major risk factor for chronic obstructive pulmonary disease (COPD). However, only a minority of cigarette smokers develop symptomatic disease. Studies of families and twins suggest that genetic factors also contribute to the development of COPD. We present a detailed literature review of the genes which have been investigated as potential risk factors for this disease.The only established genetic risk factor for COPD is homozygosity for the Z allele of the α 1 -antitrypsin gene. Heterozygotes for the Z allele may also be at increased risk. Other mutations affecting the structure of α 1 -antitrypsin or the regulation of gene expression have been identified as risk factors.Genes, including those for α 1 -antichymotrypsin, α 2 -macroglobulin, vitamin Dbinding protein and blood group antigens, have also been associated with the development of COPD. Variants of the cystic fibrosis transmembrane regulator gene have been identified as risk factors for disseminated bronchiectasis.The genetic basis to chronic obstructive pulmonary disease has begun to be elucidated and it is likely that several genes will be implicated in the pathogenesis of this disease. The knowledge gained from such studies may also prove relevant to other inflammatory diseases. Eur Respir J 1997; 10: 1380-1391. REVIEWChronic obstructive pulmonary disease (COPD) is characterized by decreased expiratory flow rates, increased pulmonary resistance and hyperinflation. The most important risk factor for the development of COPD is cigarette smoking [1]. Cigarette smoke, in combination with other factors, leads to two pathophysiological processes in the lung. The first is proteolytic destruction of the lung parenchyma, which increases the size of the airspaces; these eventually coalesce to form emphysematous spaces. The development of emphysema is associated with a loss of lung elastic recoil. The second process is inflammatory narrowing of peripheral airways, which is characterized by oedema, mucus hypersecretion and fibrosis, scarring, distortion and obliteration of peripheral airways. The loss of lung elastic recoil and the narrowing of the peripheral airways combine to decrease maximal expiratory flow from the lung and contribute to hyperinflation. In conjunction with gas exchange abnormalities, hyperinflation produces the symptoms of COPD.Despite the clear association of smoking and airway obstruction, there remains marked interindividual variation in the response to cigarette smoke. This indicates that there are additional genetic or environmental cofactors, which contribute to the development of COPD. It has been estimated that only 10-20% of chronic heavy smokers will ever develop symptomatic COPD [2,3]. Co-factors, such as childhood viral respiratory infections and environmental and occupational pollution, undoubtedly play a role in determining this susceptible subset. Furthermore, there is evidence that genetic susceptibility is of major importance. The epidemiological and clinical data that demonstrate a heredit...

Evidence for major genes influencing pulmonary function in the NHLBI Family Heart Study

“…Cigarette smoking is the most widely recognized environmental contributor to lung function decline. Occupational exposures, air pollution, a history of respiratory infections and allergens also contribute to impaired pulmonary function, but the contribution of genetics in determining lung development and pulmonary diseases also appears to be substantial [Sanford et al, 1997;Chen et al, 1996;Coultas et al, 1991]. A small proportion of patients with emphysema can attribute their lung dysfunction to a homozygous mutation in the alpha-1-antitrypsin gene that causes a deficiency in the enzyme inhibitor [Tobin et al, 1983], but genes influencing commonly occurring pulmonary dysfunction are yet to be identified.…”

Structural Characterization of Mouse Neutrophil Serine Proteases and Identification of Their Substrate Specificities

“…The contribution of NSPs to COPD was first evidenced by the observation that patients lacking ␣1-Pi, the main physiological inhibitor of neutrophil elastase, were at greater risk of developing emphysema (10,11). Subsequently, various studies reported the induction of emphysema in animal models following instillation of NSPs.…”

Different lung responses to cigarette smoke in two strains of mice sensitive to oxidants

“…However, it is well recognised that in a population of heavy smokers only 15-20% of subjects develop COPD [3]. The reason for this is unknown; however, it is likely that individual genetic risk factors may play an important role [4,5].…”