Role of Redox Homeostasis and Mitochondrial Biogenesis Genes in Chronic Obstructive Pulmonary Disease Susceptibility

Chronic obstructive pulmonary disease (COPD) is a progressive chronic disease of the respiratory tract and lungs, characterized by persistent inflammation and obstruction of the airways. Oxidative stress caused by exposure to cigarette smoke leads to mitochondrial dysfunction in airway epithelial cells, triggering apoptosis and cell aging. To identify the associations of genes encoding key regulators of cellular redox homeostasis and mitochondrial biogenesis (HMOX1, NFE2L2, PHB1, KL, GSR, and TOMM40) with COPD, a real-time PCR analysis of DNA samples from COPD patients (N = 747) and healthy individuals (N = 703) was performed. Association with COPD was established with the genes HMOX1 (rs2071749) (PFDR = 2.321 × 10–5, OR = 1.43), NFE2L2 (rs6721961) (PFDR = 0.0013, OR = 1.38), PHB1 (rs1049620) (PFDR = 2.321 × 10–5, OR = 0.81), GSR (rs1002149) (PFDR = 0.021, OR = 1.26), and TOMM40 (rs2075650) (PFDR = 0.0011, OR = 1.58). Polygenic analysis revealed informative combinations associated with COPD: FOXO1 (rs9549240)*G + HMOX1 (rs2071749)*AG + NFE2L2 (rs6721961)*TT (OR = 3.43, PFDR = 3.20 × 10–3); FOXO1 (rs9549240)*GG + GSR (rs1002149)*AA (OR = 5.91, PFDR = 2.37 × 10–4). A multivariate predictive model for COPD risk has been identified: a combination of FOXO1 (rs9549240) GG + GSR (rs1002149) AA, the genes FOXO3A (rs2253310), HMOX1 (rs2071749), KL (rs1207568), TOMM40 (rs2075650), and smoking index (P = 4.2 × 10–53, AUC = 0.829, sensitivity—65.4%, specificity—86.2%).