Genes, DNA methylation and exposures underlying COPD in never-smokers

In COPD, or chronic obstructive pulmonary disease, the lungs are damaged which makes it difficult to breathe. Smoking is the most important risk factor for developing COPD, but remarkably, 25-45% of all COPD patients worldwide have never smoked. Within this PhD project we aimed to assess the mechanisms that play a role in COPD in never-smokers. What is the role of genetic variants, epigenetic alterations (DNA-methylation) and environmental exposures, like air pollution and occupational exposures, herein? DNA-methylation can change the activity and functionality of the DNA and can be affected by exposures. It might therefore be the underlying mechanism relating exposures to lung function. The studies described in the thesisshowed that genes, DNA-methylation and environmental exposures indeed play a role in COPD in never-smokers. We have identified several (novel) genes for the development of large or small airway obstruction in specifically never-smokers. However, we found no significant differences in DNA-methylation levels between subjects with and without COPD. On the other hand, we showed that air pollution as well as occupational exposures were associated with DNA-methylation levels. For most identified DNA-methylation sites, our data suggests thatDNA-methylation induces changes in gene expression, which indicates that they may regulate the activity of these genes . In turn, this might lead to COPD depending on the function of the affected genes. Together, the information provided may ultimately lead to new therapies for treatment or prevention of COPD. Hopefully, other researchers will give more attention to never-smokers in their studies on COPD as well.