The Search for the Genetic Component of COPD: Role of the Clinical Phenotype§

Chronic obstructive pulmonary disease (COPD) is a common, complex disorder, and dissection of its individual components is considered one of the research priorities for this disease. Several lines of evidence suggest that, in spite of the massive role of cigarette smoking, common COPD is not just an environmental phenocopy of COPD associated with alpha1-antitrypsin deficiency: from the racial/ethnic variability in COPD prevalence to the individual susceptibility to cigarette smoke, from the familial aggregation of lung function levels to the familial clustering of COPD symptoms, all lines tend to point to common COPD having a genetic component. The challenge in the last three decades has been to define the borders of this component, its relative weight with respect to the environmental component, and to identify the susceptibility and/or resistance genes. Taking advantage from the knowledge, albeit limited, of the biochemical basis of COPD, a number of genetic polymorphisms have been investigated, mostly in case-control association studies. Although such a strategy is considered more successful than linkage analysis for investigating complex, non-Mendelian disorders and in spite of the considerable amount of data collected, the overall result of the genetic investigations into COPD has so far been largely disappointing. A critical evaluation of the published reports shows that a number of issues could have affected the outcome of the investigations: among such issues, the choice of the appropriate clinical phenotype is fundamental.