The Leucocyte Telomere Length, GSTM1 and GSTT1 Null Genotypes and the Risk of Chronic Obstructive Pulmonary Disease

Abstract

Chronic obstructive pulmonary disease (COPD) is characterized by chronic inflammation and oxidative stress both in the airways and blood and other organs. Elevated oxidative stress and inflammation have been reported to affect leucocyte telomere length (LTL). Glutathione S-transferase (GST) enzymes are a large family of xenobiotic-metabolizing enzymes that utilize different ROS products. We aimed to explore the link between GSTM1 and GSTT1 gene polymorphisms, LTL and COPD risk. For GSTM1, we genotyped 152 COPD patients and 131 non-affected controls; for GSTT1, we genotyped 149 COPD patients and 130 controls. We were able to assess TL for 91 patients and 88 controls. There was a significant difference in the GSTM1 null genotype frequency between the patients and controls (0.59 vs. 0.38, p ≤ 0.000), but such was not found for GSTT1 (p = 0.192). When combining both polymorphisms, we obtained a significantly greater presence of at least one null genotype among patients (0.12 vs. 0.05, p = 0.027). An association between GSTT1 and LTL was not found. COPD patients carrying the GSTM1 null genotype had shorter telomeres compared to those carrying the non-null genotype (15,720 bp vs. 22,442 bp, p = 0.008); as for the controls, it was the opposite (31,354 bp vs. 17,800 bp, p = 0.020). The significance in both groups remained when combining GSTM1 and GSTT1 (COPD (at least one null) 16,409 bp vs. COPD (non-null) 22,092 bp, p = 0.029; control (at least one null) 29,666 bp vs. control (non-null) 16,370 bp, p = 0.027). The total glutathione level in GSTM1 non-null controls was higher compared to the null genotype (15.39 ng/mL vs. 5.53 ng/mL, p = 0.002). In COPD patients, we found no association (p = 0.301). In conclusion, according to our results, GSTM1, but not GSTT1, null genotypes might play a role in leucocyte telomere shortening, and thus be involved in the pathogenesis of COPD.

Keywords: COPD; GST; polymorphisms; telomeres.

Figure 1

Genotyping of GSTM1 and GSTT1 by duplex PCRs. Non-null GSTM1 genotype individual 1 (M1+) and 3 (M1+); null GSTM1 genotype individual 2 (M1–) and 4 (M1–); non-null GSTT1 genotype individual 1 (T1+), 3 (T1+) and 4 (T1+); null GSTT1 genotype individual 2 (T1–); lines 1 and 2 (M1-0 and T1-0) are negative controls for GSTM1 and GSTT1 duplex PCRs; line 3 (marker) is a 100-bp DNA ladder (Thermo Fisher Scientific Inc, Waltham, MA, USA).

Figure 2

Leucocyte telomere length in COPD patients and controls according to presence of GSTM1 null variant. The LTL is presented as mean ± standard error of mean (SEM).

Figure 3

Leucocyte telomere length in COPD patients and controls in GSTM1 and GSTT1 combined genotypes (carriers of either GSTM1 and GSTT1 non-null genotype or at least one null genotype). The LTL is presented as mean ± standard error of mean (SEM).

Figure 4

Total glutathione levels in controls according to GSTM1 genotypes. The total glutathione is presented as mean ± standard error of mean (SEM).

Figure 5

Total glutathione levels in controls in GSTM1 and GSTT1 combined genotypes (carriers of either GSTM1 and GSTT1 non-null genotype or at least one null genotype). The total glutathione is presented as mean ± standard error of mean (SEM).