Project Summary/Abstract Mucus dysfunction plays a critical role in airway diseases like chronic bronchitis (CB) and chronic obstructive pulmonary disease (COPD). COPD affects approximately 29 million people in the US and is the third leading cause worldwide. The public health and clinical relevance of “mucus dysfunction” are better understood when one focuses on the clinical manifestations of this process —chronic cough and phlegm and chronic mucus hypersecretion/CB. Up to 32% of community-living individuals report chronic respiratory symptoms and present with normal lung function. The presence of chronic symptoms in these individuals is associated with a substantially increased risk of future hospitalization and mortality. In this proposal, we will use an objective, reproducible assessment of mucus dysfunction. We will identify and score mucus plugging on chest computed tomography (CT) scans from community-living individuals participating in two population-based studies, the Framingham Heart Study (FHS) and Coronary Artery Risk Development in Young Adults (CARDIA). In Aim 1, we will determine the clinical relevance of CT-based mucus plugging. We will evaluate the associations of mucus plugging with lung function, respiratory symptoms, and chronic bronchitis (Aim 1a); and examine whether 5-yr. Persistent CT-based mucus plugging is associated with the decline in FEV1 and future COPD (Aim 1b). In Aim 2, we will examine whether modifiable factors affect CT- based mucus plugging. We will determine whether air pollution and marijuana smoking are associated with increased odds of CT-based mucus plugging and define whether cardiorespiratory fitness is related to decrease mucus plugging. Finally, in Aim 3, we will determine genetic resilience/susceptibility to mucus dysfunction. We will use CT data from the FHS and CARDIA cohorts and genome-wide sequencing data from the TOPMed initiative to identify common and rare variants associated with CT-based mucus plugging. This study will increase our understanding of the clinical implications of an imaging-based mucus dysfunction phenotype at the population level, providing a tangible target for the interception and prevention of chronic airway disease while identifying susceptibility, risk, and protective factors for this process.