Background: Shorter telomeres and COPD are both associated with accelerated cellular aging. Previously, telomere length has been demonstrated to be associated with reduced lung function and an increased risk of COPD. Computational modeling has allowed for large-scale telomere length estimation using whole genome sequencing data from the NHLBI TOPMed consortium. We hypothesized that shorter calculated telomere length would associate with COPD affection status and COPD severity (based on Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage), and that these relationships would be modified by sex and smoking status.

Methods: Using generalized linear mixed effects model and linear mixed effects model, we tested the relationship between telomere length and spirometry-defined moderate-to-severe COPD (GOLD grades 2,3, and 4) status, GOLD levels, and forced expiratory volume in 1 second (FEV1) percent predicted using the COPDGene study. Models were adjusted for sex, age at blood draw, age2, current smoking status, smoking intensity (log pack-years), and top 10 genetic ancestry principal components. We also tested the interaction effects between telomere length and sex, age, and smoking intensity on the risk for moderate-to-severe COPD. Linear regression model was evaluated for quantitative CT scan percent emphysema. Replications were conducted using the ECLIPSE and LTRC datasets.

Results: We observed significant association between shorter telomere length and higher risk of COPD in the COPDGene cohort (P<0.0001; 95% CI: 0.67 – 0.80). The result was replicated using the LTRC cohort (P=0.041; 95% CI: 0.46-0.98). We also observed a progressive shortening of telomere by GOLD grade in the COPDGene cohort (P<0.0001; 95% CI: 0.75-0.86), which showed a similar, but non-significant, trend in the LTRC and ECLIPSE data (P=0.25 and 0.06 respectively). However, we did not observe significant effect modification by sex, age or pack-years of smoking on the association of telomere length on COPD status. There was significant association between telomere length and percent emphysema in the COPDGene study (p-value = 3.37e-04).

Conclusion: Shorter telomere length associates with the risk of moderate-to-severe COPD and demonstrates shortening with increasing COPD severity. Decelerating telomere attrition may represent an important therapeutic target for mitigating COPD progression in smokers.