Telomeres: the link between smoking, COPD and lung cancer?

Abstract

Aims: To determine if there is a difference in telomere length between smokers with four different health outcomes: lung cancer, COPD, lung cancer and COPD, and ‘healthy’ smokers. Also, to determine the risk of lung cancer and COPD associated with the SNPs rs754388 and rs4846480. Methods: The available cohort is a unique mix of healthy and diseased smokers matched for age and smoking exposure. Telomere length was measured indirectly using a qPCR assay in a subpopulation of 285 samples matched for age, smoking exposure, and disease state to the entire cohort. The assay determines the effective concentration of telomeric repeats and a single copy reference gene (albumin), allowing for calculation of the T/S ratio and determination of relative telomere length between individuals. Genotypic determination of the SNPs was undertaken for the entire cohort via a Taqman based qPCR assay with probes specific to either allele for each SNP. Results: There was a statistically significant shortening of telomeres in all of the disease groups. There was a rightward shift in the distribution of T/S ratio in the controls. Division of telomere length into long-, medium-, and short-telomeres showed a statistically significant excess of short telomeres and deficit in the disease groups. There were statistically significant differences between the control and disease groups, and between the sub-population and the same group in the entire cohort. However, there was no significant relationship between any of the demographic characteristics studied and T/S ratio. Decreased risk of lung cancer and COPD was associated with the GG genotype of rs754388, while an increased risk of lung cancer only was associated with the TT genotype of rs4846480. Conclusions: Both lung cancer and COPD are associated with shortened telomeres, likely due to the genomic instability and senescence (with subsequent pro-inflammatory microenvironment) imparted by critically short telomeres. None of the demographic differences had a significant association with T/S ratio so their confounding effect should be minimal. Increase in lung cancer and COPD risk is likely due to an inflammatory affect linked to rs754388, while the effect linked to rs4846480 likely only affects the cancer-associated activity of TGFΒ2.