Although cigarette smoke exposure is the predominant risk factor for development of COPD, occupational exposure to heavy dust or fumes or exposure to smoke from incomplete combustion of biomass fuels like wood smoke are likely to be equally as dangerous. Significant research interest focuses on the relationship between airway hyper-reactivity and development of COPD. Hyper-reactivity appears to occur after obstructive lung disease arises. Whether adolescent asthma and antigen exposure predispose to COPD in adults is unclear.
Chronic cough and sputum production may predict a subset of smokers with increased risk for developing COPD. Whether the quantity of environmental exposure relates to sputum production or cough is unknown; in patients with established COPD, cough and sputum production are more common in current smokers. The role of early-life lung infections as an environmental risk for development COPD has been debated. Although there are models of injury during lung development that lead to alveolar hypoplasia, a direct relationship between risk of COPD and common childhood lung infections is not established.
Longitudinal studies suggest that early smoking by females may have a greater effect on maximal lung development than it does with males, and the effect may continue for a few years longer than it does in men, placing adolescent women at a much lower starting point for lung function before smoking-related declines occur. Whether females are at greater risk of early COPD because of a more rapid decline in function or because of the effects of smoking on lung development is unclear. Multiple studies have suggested a greater prevalence of severe COPD in women. Although women have historically had lower exposures to tobacco smoke and environmental fumes than men have, this may change as more adolescent women decide to smoke.
The most significant genetic risk factor for development of COPD is deficiency in A1AT (Serpin A1). Although the enzyme inhibits trypsin, its ability to inhibit neutrophil elastase is key to preventing development of lung disease. Neutrophils entering the lungs of patients with A1AT deficiency cause more lung destruction than they do in those without the deficiency because of unopposed enzyme activity in areas of the lung with low inhibitor levels (Figure 2).
Wide, unexplained variations in disease severity in individuals with comparable levels of A1AT deficiency, even after adjusting for smoking history, demonstrate the daunting task of establishing causality of other genetic polymorphisms of lesser pathogenic impact in the production of lung disease. The frequency of lung function testing in individuals with early-onset emphysema or atypical asthma who are tested for A1AT deficiency is nearly as low as the frequency of lung function testing in symptomatic smokers. Subjects suspected of having A1AT deficiency can be easily screened with a simple blood test available at most institutions. There is little reason for limiting screening of appropriate patients for this uncommon--but not rare--genetic disorder.
Differences in the levels of circulating A1AT protein (phenotype) are observed among individuals with the less severe S allele and those with the more severe Z allele. Individuals who have an SZ genotype and an SZ phenotype are at a lower risk for development of COPD than are those with the ZZ phenotype. Whether individuals heterozygous for A1AT deficiency (MZ genotype) are at increased risk of accelerated emphysema is a subject of much debate.
Although concern about disease is less in MZ heterozygotes, in the absence of environmental risk, accumulating data suggest smokers who have as much as 50 percent of the normal circulating protein (MZ "carriers") are at increased risk. Given that smoking is uncommon in individuals who know they have severe A1AT deficiency (ZZ and SZ phenotypes), the low absolute risk of having MZ or SS genotypes should not limit efforts to caution individuals with lower risk genotypes and to discuss the familial risk of smoking with their children and siblings.
Two basic approaches have been utilized to search for other genetic risk factors in subjects with COPD: the candidate gene approach and genome-wide association studies (GWAS):
The candidate gene approach, in which a gene suspected of a disease relationship (based on biologic plausibility) is investigated in a fair-sized cohort, is the more common approach. Important information may be uncovered using this technique, as significant positive findings may be observed even in fairly small cohorts. Unfortunately, failure to confirm positive findings often leads to more speculation regarding the roles of ethnicity, phenotypes, and other factors specific to the population studied. Given the data on phenotypic presentation in A1AT deficiency, this speculation is not surprising.
GWAS have been performed with widespread collections of biologic samples for genetic testing from large cohorts of patients with COPD. This approach, which is not hypothesis-driven, offers unique and often unexpected results. Like the candidate gene approach, GWAS may lead to erroneous conclusions, despite study of large populations. The technique is based on locations of gene polymorphisms, where there are large areas of linkage disequilibrium; therefore, while results may identify a region with a gene that can be potentially implicated in disease pathogenesis, the region may contain other genes related to lung development or smoking behavior.
For example, the leading candidate genes for development of both lung cancer and COPD are members of a gene family of nicotinic acetylcholine receptor alpha chains (CHRNA). However, given the potential for members of this gene family to interact with smoking behavior, causation and risk may be only indirectly related.
Other findings from GWAS suggest that we have overlooked the effect of abnormal lung development on subsequent risk for COPD (and asthma). Some genes discovered as genetic modifiers of COPD risk are also important in determining the heritability of lung function in individuals without disease. An example is the hedgehog interacting protein (HHIP), which is part of a pathway involved in limb patterning and embryonic development. An area near the HHIP gene is associated with both lung disease and a reduction in lung function in individuals with no overt disease. These findings reflect the complexity of the genetic risk for COPD, environmental influences, and our historical use of arbitrary measures (e.g., a fixed ratio of FEV1 to FVC) in defining the presence of disease (Figure 3).
With all of these caveats noted, genetic associations suggest that gene variations that influence antioxidants, protease/antiprotease balance, lung development, and cigarette smoking are important contributors to development of COPD. However, none of these suspected genetic modifiers has yet reached a level of clinical applicability to warrant patient screening or counseling to reduce the risk of COPD.
Reposted with permission from Decision Support in Medicine, LLC.