What can naturally occurring mutations tell us about the pathogenesis of COPD?

The airway and emphysema phenotypes of chronic obstructive pulmonary disease (COPD) cluster in susceptible families. Some of this clustering is likely to be the result of shared genetic factors. There are a number of relatively rare syndromes that predispose to COPD, and a growing number of association and linkage studies that have assessed the genetic factors that predispose smokers to airflow obstruction. A review of the literature was performed to determine what has been learnt about the factors and pathways that predispose some individuals to progressive airflow obstruction while others are relatively resistant. There is very strong evidence that the integrity of the extracellular matrix, and in particular the elastin fibres, are important in the pathogenesis of COPD. There is also support for the role of proteinase-antiproteinase imbalance and probably oxidative stress. However, many of the genetic studies have focused on pathways that have already been implicated in disease. It is now essential that future studies take advantage of multiple large cohorts that have been phenotyped for both airways disease and emphysema, and use modern technology to perform unbiased genome-wide analyses of genetic variation in COPD. Only then will we have new insights into the pathways that underlie this common condition.