DNA methylation signature and epigenetic age of severe COPD

Background: In patients with COPD, tobacco smoking is associated with epigenetic changes (CpG methylation) and accelerated ageing (shortened telomeres). We previously reported that lung DNA methylation profiles in COPD differ according to the severity of airflow limitation. Here we aimed to identify the relationship between the severity of airflow limitation, blood epigenetic changes and accelerated ageing in patients with COPD. Methods: DNA was extracted from blood of COPD patients with mild-moderate (n=184) and severe-very severe (n= 143) airflow limitation. DNA methylation was assessed with the EPIC array (Illumina). The epigenetic clock(definition) PhenoAge was used to determine the biological age of each COPD patient. Multivariate linear regression adjusted for chronological age, sex, pack-year and current smoking status, was used to determine the associations with FEV1 % ref. Results: We found 475 CpG-sites (279 genes) significantly associated (p<9E-8) with airflow limitation severity (FEV1% ref.). These genes are mainly involved in angiogenesis and immune cell activation. The epigenetic clock showed that, compared with COPD patients with mild-moderate airflow limitation, those with severe-very and severe airflow limitation had an accelerated biological ageing, independendently of smoking. Conclusions: COPD patients present a blood DNA methylation signature associated with the severity of airflow limitation independent of the smoking exposure. Furthermore, those patients with severe-very and severe airflow limitation also show an accelerated biological ageing.