Human airway branch variation and chronic obstructive pulmonary disease

Abstract

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.

Keywords: airway branching; chronic obstructive pulmonary disease; computed tomography; fibroblast growth factor.

Fig. 1.

Representative 3D airway reconstructions from chest CT scans of participants with standard lower-lobe anatomy (A), an accessory subsuperior airway branch variant (B), and absent right medial-basal airway branch variant (C). Standard lower-lobe segmental airway anatomy was defined as the presence of right and left superior, anterior-basal, lateral-basal, and posterior-basal segmental airways; the presence of the right medial-basal airway; absence of the left medial-basal airway; and absence of subsuperior segmental airway. (See SI Appendix, Fig. S2 for details.) A variant lower-lobe segmental airway, defined as any deviation from standard anatomy, with a prevalence above 5% in the MESA Lung Study was considered common. The remaining 4% of participants in the MESA Lung Study had rare or combinations of variants.

Fig. 2.

Inhaled 3He magnetic resonance-assessed ADCs among participants with an accessory subsuperior airway and standard anatomy. Shown are representative anterior-to-posterior coronal ADC heat maps from a participant with an accessory subsuperior airway (Right) and a participant with standard anatomy (Left). Participants with an accessory subsuperior airway demonstrated higher ADCs than participants with standard anatomy matched for gender, height, and COPD status. See SI Appendix, Table S11 for mean differences in CT-assessed percent emphysema.

Fig. 3.

Mean differences in cross-sectional airway lumen areas by lobe and by anatomical level among participants with an absent right medial-basal airway branch variant (dashed circle) compared with standard anatomy in unaffected lobes. Airway lumen area comparisons are adjusted for lung volume. All mean differences were statistically significant (P < 0.01). See SI Appendix, Fig. S4 for standard airway anatomy lumen areas and mean differences with 95% CI.

Fig. 4.

Regional association plot of candidate SNPs located within the FGF10 gene and the absent right medial-basal airway variant. Candidate SNPs were selected a priori based on their location within genes implicated in airway morphogenesis (11 genes, 109 SNPs). Genotyping: Affymetrix 6.0, excluding MAF <0.5, missingness per SNP >0.1, missingness per subject >0.1, and linkage disequilibrium >0.7. Candidate SNPs within FGF10 are indicated by diamond symbols. The degree of linkage disequilibrium with rs980510 is indicated by the R² color scale. Square symbols indicate regional FGF10 SNPs not included in the candidate gene analysis. ORs and P values were calculated using an additive allelic model for each race/ethnic group, adjusted for gender and genetic ancestry principle components, and pooled by random effects meta-analysis. I² is an index of effect measure heterogeneity by race/ethnicity. The Bonferroni P threshold of 4.59E−04 [−log(4.59E−04) = 3.34] is indicated by the dashed line.