Lung RNA-sequencing to understand the heterogeneity of COPD

Rationale: Chronic Obstructive Pulmonary Disease (COPD) is a complex and heterogeneous disease whose pathobiology is not fully understood. Objectives: To characterize and contrast the pulmonary mRNA expression in former smokers with COPD (mild=15; severe-very severe=16) and healthy controls (never smokers=11). Methods: Lung tissue was obtained from individuals undergoing thoracic resectional surgery (mostly because of lung cancer) or lung transplantation explants. Paired end TruSEQ RNASeq libraries were constructed and analyzed with an Illumina HiSeq. Sequencing analysis and differential gene expression was done with DESeq2, and in order to find modules of co-expressed genes related to clinical traits (airflow limitation severity, BMI and PackYear) weighted correlation networks were constructed with the whole matrix. Measurements and Main Results: The number of differentially expressed genes was higher between non-smokers vs. severe COPD (n=675), followed by mild COPD vs. severe COPD (n=391), while the expression profile of non-smokers vs. mild COPD was the most similar. Network weighted co-expression analysis identified 19 modules, 5 of them were associated to the presence of airflow limitation and its severity but not smoking or BMI. Key genes are validated in a second cohort of individuals. Conclusions: Severe airflow limitation represents a distinctive transcriptomic signature in comparison to mild COPD and non-smokers. Transcriptomic changes of mild former smokers with COPD vs. non-smokers are more heterogeneous. Supported, in part, Instituto de Salud Carlos III (PI15/00799), CP (16/00039) and a grant from MSD.