Associations of the NRF2/KEAP1 pathway and antioxidant defense gene polymorphisms with chronic obstructive pulmonary disease

• Published in: Gene 2019-04, Vol.692, p.102-112
• Main Authors: Korytina, Gulnaz F., Akhmadishina, Leysan Z., Aznabaeva, Yulia G., Kochetova, Olga V., Zagidullin, Naufal Sh, Kzhyshkowska, Julia G., Zagidullin, Shamil Z., Viktorova, Tatyana V.
• Format: Article
• Language: English
• Subjects: Antioxidant defense system genes; Chronic obstructive pulmonary disease; Gene-by-environment interaction; Oxidative stress
• ISSN: 0378-1119; 1879-0038
• DOI: 10.1016/j.gene.2018.12.061

Chronic obstructive pulmonary disease (COPD) is a complex chronic inflammatory disease of the respiratory system affecting primarily distal respiratory pathways and lung parenchyma. This work was designed as a case-control study aimed at investigating the association of the NRF2/KEAP1 signaling system, and antioxidant defense gene polymorphisms with COPD in population from Russia. Ten SNPs: NFE2L2 (rs35652124), KEAP1 (rs1048290), MPO (rs2333227), PRNP (rs1799990), PTGR1 (rs2273788), HSPA1A (rs1008438), TXNRD2 (rs1139793), GSR (rs1002149), SIRT2 (rs10410544), and PTGS1 (rs1330344) were genotyped by the real-time polymerase chain reaction (TaqMan assays) in a case-control study (425 COPD patients and 457 controls, from the same region of Russia, representatives of Tatar population). Logistic regression was used to detect the association of SNPs in different models. Linear regression analyses were performed to estimate the relationship between SNPs and lung function parameters and smoking pack-years. In our population, a significant associations of KEAP1 (rs1048290) (P = 0.0015, OR = 0.72 in additive model), HSPA1A (rs1008438) (P = 0.006, OR = 2.26 in recessive model), GSR (rs1002149) (P = 0.037, OR = 1.31 in additive model) with COPD were revealed. NFE2L2 (rs35652124), PRNP (rs1799990), and HSPA1A (rs1008438) were significantly associated with COPD only in smokers. In nonsmokers, significant association was established for GSR (rs1002149). KEAP1 (rs1048290) was associated with COPD in both groups. The relationship between KEAP1 (rs1048290), NFE2L2 (rs35652124), and HSPA1A (rs1008438) and smoking pack-years was found (P = 0.005, P = 0.0028, P = 0.015). A significant genotype-dependent variation of forced vital capacity and forced expiratory volume in 1 s was observed for SIRT2 (rs10410544) (P = 0.04), NFE2L2 (rs35652124) (P = 0.028), and PRNP (rs1799990) (P = 0.044). •SNPs in NRF2/KEAP1 pathway play an important role in COPD.•NFE2L2 rs35652124, KEAP1 rs1048290, PRNP rs1799990, HSPA1A rs1008438 were associated with COPD in smokers.•The smoking index was affected by KEAP1 rs1048290, NFE2L2 rs35652124, HSPA1A rs1008438.•GSR rs1002149 was associated with COPD in non-smokers.•SIRT2 rs10410544, NFE2L2 rs35652124, PRNP rs1799990 were associated with FVC and FEV1.