Chronic Obstructive Pulmonary Disease in Non-Smokers

Chronic obstructive pulmonary disease (COPD) contributes significantly to morbidity and mortality among non-smokers, but this group has been excluded from major COPD studies with lung imaging. Risk factors for COPD in non-smokers include age, prior asthma, environmental exposures and genetic susceptibility; however, these factors alone explain only a small proportion of COPD risk. In the Multi-Ethnic Study of Atherosclerosis (MESA) Lung Study, we recently demonstrated that a common airway anatomy variant was associated with higher COPD prevalence and altered regional airflow. Findings were consistent among smokers and non-smokers but underpowered in the latter group. The hypothesized mechanisms underlying COPD and airway anatomy include: i) proximal airway variants increasing regional resistance to flow and particulate matter deposition; and ii) proximal airway variants indicating altered distal airway branching. Preliminary computational fluid dynamic (CFD) models suggest lower regional airflow and increased particle transit to the lung periphery with airway variants increasing risk in non-smokers and smokers, respectively. Further, the PI has performed additional pilot work to suggest that proximal airway variants increasing COPD risk in non-smokers reflect diffusely altered airway anatomy. This preliminary work lays the basis for understanding the mechanism of risk and warrants thorough investigation in the proposed project using state-of-the-art CFD, and a novel quantitative metric of airway branch density. Variant airway anatomy has developmental and genetic origins and may provide refined phenotypes for genetic investigation. Preliminary work identified variants in a gene implicated in airway development associated with variant airway anatomy on computed tomography (CT).