Grant: Project Grant

Chronic obstructive pulmonary disease (COPD) is characterized by airflow limitation (inability to empty the lungs), and is a major public health problem in Canada and globally. Smoking is the best known COPD risk factor, and reducing smoking is essential to public health. There are, however, some inconvenient truths about COPD that we must confront if we want to meaningfully lower the public health burden of COPD. First, smoking rates in several countries have declined by 50% over the past 5 decades (including Canada), but the corresponding COPD mortality is not declining. Second, one-quarter of COPD occurs in never-smokers (27% in Canada). Third, only a minority of lifetime smokers develop COPD. As COPD mortality continues to increase, understanding major determinants of COPD susceptibility and progression beyond smoking is critical. A growing body of evidence suggests that dysanapsis is a major contributor to COPD. Dysanapsis refers to the disproportionate scaling of airway-to-lung dimensions. Since airway dimensions determine airflow resistance, disproportionate scaling of airway-to-lung dimensions (dysanapsis) may contribute to airflow limitation. We recently developed and validated a computed tomography (CT) measure of dysanapsis. This dysanapsis measure explains more airflow limitation than all traditional COPD risk factors including smoking. Furthermore, our dysanapsis measure was strongly associated with the COPD Genetic Risk Score - a composite genetic score based on 97 known COPD genes, suggesting that genetic pathways contribute to dysanapsis. Unraveling the mechanisms of dysanapsis - a major contributor to COPD on par with smoking - is essential in order to develop early life interventions to promote healthy lungs for life. We propose a genome-wide association study of CT-measured dysanapsis among older adults, and testing whether these polymorphisms predict airflow limitation and respiratory events in children.