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Blood biomarkers in chronic obstructive pulmonary disease (COPD)

University of British Columbia

Chronic obstructive pulmonary disease(COPD) is an age-related disease and demonstrates many biological hallmarks of aging including telomere shortening and epigenetic alterations. This study examined the relationship between telomere length, reflecting replicative senescence, and Alu and LINE-1(L1) methylation, reflecting one of the major epigenetic changes of peripheral blood leukocytes, and clinical outcomes, including lung function, health status, rate of exacerbations, and risk of mortality with different COPD stages. Using quantitative polymerase chain reaction, we measured the absolute telomere length(aTL) of DNA extracted from blood samples of 576 participants with moderate-to-severe COPD treated with either azithromycin or placebo in the Macrolide Azithromycin for Prevention of Exacerbations of COPD(MACRO) study. Using bisulfite pyrosequencing, we measured the percentage(%) Alu and L1 methylation of DNA extracted from blood samples of 495 participants with acute-exacerbating-COPD(AECOPD) in the COPD Rapid Transition Program(RTP), and 373 participants with non-COPD in the Canadian Cohort of Obstructive Lung Disease(CanCOLD). Participants with shorter aTL (defined as below the median cutoff value for aTL) had worse health status as defined by higher St. George’s Respiratory Questionnaire(SGRQ) scores (P=0.034). In the placebo arm, the rate of exacerbations (P=0.002) and the risk of mortality (P=0.015) were significantly higher in the shorter telomere group than in the longer telomere group. % Alu methylation was significantly related to FEV₁% predicted, FEV₁ in liters(L) and FEV₁/FVC ratio (P<0.0001), and when the cohort was divided into quartiles, the higher the quartile the better the FEV1 % predicted and FEV₁(L) (P<0.0001). % Alu methylation was also significantly related to the decline of FEV₁% predicted (%/year), (P=0.004) and FEV₁/FVC ratio (%/year)(P=0.007) as well as to total and sub-domain SGRQ scores (P<0.0001 except the Impact score P=0.041). % L1 methylation was significantly different between different states of COPD: stable-, non- & AE-COPD, where the non-COPD participants had the highest percentage of methylation and AECOPD participants demonstrated the lowest (P<0.0001). Together these data suggest that senescence blood biomarkers in COPD patients are associated with poor health outcomes. These relatively simple blood measurements may represent a potential source of clinically translatable biomarkers for identifying patients at high risk of morbidity and mortality in COPD.

Text

2020-07-31

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/71076

Experimental Medicine

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/