DNA methylation is associated with lung function levels in never-smokers

Active smoking is the main risk factor for COPD and epigenetic mechanisms such as DNA methylation upon exposure to cigarette smoke have been suggested to play a role in this association. However, 25-45% of the subjects with COPD have never smoked and it is unclear whether epigenetics also plays a role in never smokers. Therefore, we aimed to identify CpG-sites that are associated with lung function levels in never-smokers. We determined genome-wide DNA methylation levels of 400,220 CpG-sites (Illumina 450K) in blood of never-smokers of 2 independent cohorts, LifeLines (N=903) and Rotterdam Study (N=206). We meta-analyzed the cohort-specific methylation results to identify differentially methylated CpG-sites with lung function levels (FEV1/FVC). Seven CpG-sites were associated with lung function levels in never-smokers (p-value < 10-5). Among the annotated CpG-sites were cg12241532 (PFKP), cg23859313 (ZFYVE28) and cg01979287 (MRPL38). Since this differential DNA methylation cannot be explained by smoking, we revealed in a post-hoc analysis if the CpG-sites were differentially methylated upon passive smoke exposure. In here, we found that cg01979287, annotated to MRPL38, which is known to be involved in protein synthesis in mitochondria, was significantly higher methylated in the subjects that were exposed to passive smoke compared to non-exposed. With the identification of 7 differentially methylated CpG-sites with lung function levels in never-smokers, our data suggests that factors other than smoking affect lung function levels via DNA methylation. The association between methylation of cg01979287 and passive smoke exposure implies that the role of environmental exposure should be further explored.