Genetic and environmental modulation of chronic obstructive pulmonary disease

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Abstract

Chronic Obstructive Pulmonary Disease (COPD) is a leading cause of morbidity and mortality throughout a large part of the western world. Although personal tobacco use has been implicated in a large number of these cases, it is also true that only a fraction of smokers ever develop respiratory problems. Therefore, the question of host susceptibility and other environmental factors should be considered. This paper will briefly review evidence for host susceptibility to COPD, review evidence for additional environmental risk factors for the development of COPD, and give an example of environmental interactions with a known genetic risk factor that further increase the risk of COPD.

Introduction

Both genetic (Silverman et al., 1998, Barnes, 1999) and environmental (Kauffman et al., 1982, Love and Miller, 1982, Sparrow et al., 1982, Wegman et al., 1982, Becklake, 1985, Korn et al., 1987, Becklake, 1989, Cowie and Mabena, 1991, Xu et al., 1992, Christiani et al., 1994) factors affect an individual's risk for chronic obstructive pulmonary disease (COPD), a disorder that broadly includes the range of pulmonary pathology from bronchial inflammation to emphysema (ATS, 1995). Less well studied is the manner in which environmental factors interact with genetic factors in contributing to COPD risk. This is partially due to the pitfalls and limitations of current methodological approaches to dissecting the gene and environment contributions to any complex disease in which multiple genes and multiple exposures may alter the phenotypic expression of the disorder. What follows is a discussion of: (1) evidence for genetic susceptibility for COPD; (2) evidence of environmental risk for COPD; (3) evidence for a genetic and environmental interaction for the risk of COPD based on our recent studies of the best understood form of genetic susceptibility to COPD: severe alpha1-antitrypsin (α1AT) deficiency.

Section snippets

Genetic risk for COPD

Epidemiologic studies have demonstrated aggregation of COPD among relatives, but without clear Mendelian inheritance. Household aggregations of chronic bronchitis were found in a randomly selected group in Massachusetts (Tager et al., 1976). In addition, FEV1 was significantly correlated between siblings and between female children and their parents, but less clearly between spouses. Using case-control methodology, researchers have shown that chronic bronchitis and lower FEV1 were more

Environmental Risk for COPD

Tobacco smoking is recognized as the single most important risk factor for development of COPD (ATS, 1995). This review will not focus on the ample evidence linking personal tobacco smoke with COPD, but will focus on other important contributing environmental factors including dust, fumes, and environmental tobacco smoke (ETS).

The role of occupational and environmental exposures in airway disease was supported in three large well-designed community studies. Specifically, the Harvard six cities

Genetic and environment interactions in α1AT deficiency

The case of α1AT deficiency is illustrative and serves as a model disorder in which to investigate effects of environmental factors in a genetically susceptible patient population. Tobacco smoking is the principal environmental risk factor associated with the development of chronic airflow obstruction individuals with severe α1AT deficiency, phenotype PI*Z (Larsson, 1978, Tobin et al., 1983, Janoff, 1985, Silverman et al., 1989). The mean age of onset of symptoms is 30–40 years of age in

Implications for future studies

COPD is the consequence of an overriding effect of environmental exposures on the lung. Several decades of research have successfully identified a number of those exposures, especially tobacco smoke. It appears that the extent of the lung damage caused by those insults may be modulated by genetic or other host factors. Further identification of genetic factors predisposing certain individuals to increased COPD risk is an important goal of the ongoing research using DNA microarrays, differential

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