Human airway branch variation and chronic obstructive pulmonary disease

Significance The human airway tree is a filter of noxious particulate matter, the primary cause of chronic obstructive pulmonary disease (COPD). We demonstrate that variation in central airway tree branching occurs in over one-quarter of the general population and increases COPD susceptibility, particularly among smokers. We show that these central airway branch variants are biomarkers of altered distal lung structure, the primary site of COPD pathobiology. Finally, we demonstrate the heritability of central airway branch variants within families and identify and replicate an association with FGF10. These findings suggest that central airway branch variants, easily detectable by computed tomography, represent heritable biomarkers of widely altered lung structure and a COPD susceptibility factor. Susceptibility to chronic obstructive pulmonary disease (COPD) beyond cigarette smoking is incompletely understood, although several genetic variants associated with COPD are known to regulate airway branch development. We demonstrate that in vivo central airway branch variants are present in 26.5% of the general population, are unchanged over 10 y, and exhibit strong familial aggregation. The most common airway branch variant is associated with COPD in two cohorts (n = 5,054), with greater central airway bifurcation density, and with emphysema throughout the lung. The second most common airway branch variant is associated with COPD among smokers, with narrower airway lumens in all lobes, and with genetic polymorphisms within the FGF10 gene. We conclude that central airway branch variation, readily detected by computed tomography, is a biomarker of widely altered lung structure with a genetic basis and represents a COPD susceptibility factor.