Beyond (epi)genetic association studies: functional studies of COPD susceptibility genes

Chronic obstructive pulmonary disease (COPD) is a disease of the lungs accompanied by chronic inflammatory processes of the (small) airways, which is currently the third leading cause of death worldwide. The current treatment options reduce symptoms but there is no cure for COPD. Therefore, to develop effective treatments, more research is needed to further understand the pathogenesis of COPD.Exposure to environmental factors, particularly cigarette smoke, is the most common risk factor for COPD. However, more than 25% of the COPD patients have never smoked, suggesting that genetic susceptibility might play a role as well. It has been discovered that gene FAM13A, AHRR and HHIP are associated with COPD or lung function. However, it is unclear how these genes contribute to COPD.This thesis describes functional studies of the genes FAM13A, AHRR and HHIP in COPD. We investigated the role of these genes in the barrier function of the airway epithelium, mitochondrial function, cell death and the repair of both the airway epithelium and alveoli. Our results show that different expression of COPD susceptibility genes FAM13A and HHIP, as well as different regulation of the gene AHRR may play a role in the abnormalities observed in the airway epithelium of COPD patients. These genes may be involved in the regulation of mitochondrial function, barrier function, immunogenic cell death and cell regenerative responses in the epithelial cells of human lungs. With these studies, we took the first step in understanding the role of susceptibility genes in COPD pathogenesis