Genes related to emphysema are enriched for ubiquitination pathways

Increased small airway resistance and decreased lung elasticity contribute to the airflow limitation in chronic obstructive pulmonary disease (COPD). The lesion that corresponds to loss of lung elasticity is emphysema; the small airway obstruction is due to inflammatory narrowing and obliteration. Despite their convergence in altered physiology, different mechanisms contribute to these processes. The relationships between gene expression and these specific phenotypes may be more revealing than comparison with lung function. We measured the ratio of alveolar surface area to lung volume (SA/V) in lung tissue from 43 smokers. Two samples from 21 subjects, in which SA/V differed by > 49 cm2/mL were profiled to select genes whose expression correlated with SA/V. The level of expression of 181 transcripts was related to SA/V ( p< 0.05). The relationship between expression of these transcripts and SA/V was tested in the 22 remaining subjects as a replication. Thirty of the 181 genes remained significantly associated with SA/V (P<0.05) and the direction of association was the same in 164/181. Pathway and network analysis revealed enrichment of genes involved in protein ubiquitination, and western blotting showed altered expression of genes involved in protein ubiquitination in obstructed individuals. These data implicate modified protein ubiquitination and degradation as a potentially important pathway in the pathogenesis of emphysema. Raw data not available for this study RNA from 8 GOLD 0 subjects (non-obstructed smokers) was pooled to form the reference to compare with each individual sample. mRNA from the specimens was profiled using the same Agilent array design (Platform: GPL3991. Human 3.0 A1 containing 23,757 probe-sets) and samples are derived from the same patient cohort as those in GSE8500 study. Since a “batch effect” confounded the results, we performed a very conservative phase/batch adjustment step before commencing with statistical analysis (information will be provided in the future online supplement).