LAUSR

Background: Tobacco smoking is the main environmental risk factor for COPD. Smoking exposure alters DNA methylation, which in turn regulates gene transcription. Yet, not all smokers develop COPD. This study sought to get further insight into the relationship between smoking status (former, current, ever), presence and severity of COPD, and lung tissue DNA methylation and gene expression patterns. Methods: We used the Illumina 850k platform to determine the lung tissue methylation profile in 189 lung tissue samples obtained from never smokers, former smokers and current smokers, with and without COPD. In some of them (n=111, 59%) lung mRNA expression was also determined (Affymetrix arrays). Results: Main results showed that: (1) the lung DNA methylation profile is profoundly altered in COPD, especially in patients with severe-very severe airflow limitation, particularly in relation to some specific cellular mechanisms, such as cell shape (ARAP1, MKLN1, NGF, NTRK2, RHOG) and surfactant homeostasis (EPAS1 and LPCAT1); (2) current smoking induces specific DNA methylation changes that overlap only marginally (20%) with those seen in former smokers with mild-moderate COPD and almost nothing (4%) with those determined in former smokers with severe-very severe COPD; and, finally, (3) we identified 22 genes whose expression (mRNA levels) correlates with differential methylation. Conclusions: The lung methylation profile observed in COPD varies with the severity of airflow limitation, being more (albeit not much) “smoking-related” in mild-moderate COPD. These changes translate into specific gene expression differences that may be associated to the pathobiology of COPD.