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 ( = 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 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.

Structural and functional assessments of COPD populations via image registration and unsupervised machine learning

“…In this present study, we compared former and current smokers from SPIROMICS to assess the variation of airway branches and their associations with imaging-based clusters. First, the prevalence of airway variants among clusters were consistent with those of the general population reported by Smith et al (99) with Acc. B* and Abs.…”

Fgf10 Signaling in Lung Development, Homeostasis, Disease, and Repair After Injury

“…In the former syndrome, patients exhibit irreversible airway obstruction, indicating that genetic variants affecting the FGF10 signaling pathway are important determinants of lung function which ultimately contribute to COPD ( Klar et al, 2011 ). Notably, an airway branch variant with absence of the right medial-basal airway associated with polymorphisms within the FGF10 gene is associated with COPD among smokers ( Smith et al, 2018 ). Interestingly, increased nuclear YAP levels, along with FGFR2B and WNT7b expression, were observed in squamous metaplastic areas within the airway epithelium of COPD subjects ( Volckaert et al, 2017 ), suggesting that the Hippo pathway is inactivated to induce FGF10 expression and BSC amplification in human COPD.…”

<p>Chronic Obstructive Pulmonary Disease in Women: A Biologically Focused Review with a Systematic Search Strategy</p>

“…Changes in lung structure could also influence disease presentation. [56][57][58] Genome-wide, single-nucleotide polymorphism (SNP)-by-sex interaction testing demonstrated that an SNP in the cadherin EGF LAG seven-pass G-type receptor 1 (CELSR1) gene was associated with COPD in women but not in men. 59 CELSR1 is involved in early lung development, which could ultimately contribute to structural differences in adulthood.…”