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Airway and parenchymal disease in chronic obstructive pulmonary disease are distinct phenotypes.

The relative importance of genetic factors and tobacco smoking intensity in the pathogenesis of the airway disease and emphysematous components of chronic obstructive pulmonary disease (COPD) is unknown. We addressed this question in a family-based study that recruited probands (FEV1 5 pack-year smoking history) and their current/ex-smoking siblings. The family-based design allowed us to test the relationship between COPD phenotype (emphysema or small airway disease) in a proband and his or her siblings. Subjects completed a questionnaire and underwent spirometry, and a subset of participants underwent chest computed tomography (CT) scans. 
 
Results: The number of pack-years was only weakly correlated with FEV1 in 634 individuals with emphysema, as assessed by radiologist scoring of chest CT scans (r = −0.09, p = 0.02). The amount of emphysema on CT scan was inversely related to FEV1 (p < 0.001), but there was no relationship between pack-years and amount of emphysema. Emphysema was more prevalent in the siblings of probands with emphysema (41.7%) than in siblings of nonemphysema probands (23.6%, p < 0.001); this was independent of pack-years smoked (adjusted odds ratio, 2.12; p = 0.03). In 482 individuals without emphysema, FEV1 was correlated with pack-years smoked (r = −0.38, p < 0.0001). The correlation between pack-years and FEV1 was particularly strong (r = −0.58, p < 0.0001) in 48 siblings who were from families in which the proband had predominantly small airway disease. 
 
These data suggest that emphysema and airway-related COPD are distinct phenotypes and have different relationships with smoking. Moreover, differences in amount of emphysema are not explained by cumulative smoking, suggesting a complex gene–environment interaction.