Epigenetic marker of telomeric age is associated with exacerbations and hospitalizations in chronic obstructive pulmonary disease

Ana I. Hernández Cordero; Chen Xi Yang; Xuan Li; Stephen Milne; Virginia Chen; Zsuzsanna Hollander; Raymond Ng; Gerard J. Criner; Prescott G. Woodruff; Stephen C. Lazarus; John E. Connett; Mei Lan K. Han; Fernando J. Martinez; Robert M. Reed; S. F.Paul Man; Janice M. Leung; Don D. Sin

doi:10.1186/s12931-021-01911-9

Epigenetic marker of telomeric age is associated with exacerbations and hospitalizations in chronic obstructive pulmonary disease

Ana I. Hernández Cordero, Chen Xi Yang, Xuan Li, Stephen Milne, Virginia Chen, Zsuzsanna Hollander, Raymond Ng, Gerard J. Criner, Prescott G. Woodruff, Stephen C. Lazarus, John E. Connett, Mei Lan K. Han, Fernando J. Martinez, Robert M. Reed, S. F.Paul Man, Janice M. Leung, Don D. Sin

Biostatistics

Research output: Contribution to journal › Article › peer-review

4 Scopus citations

Abstract

Background: Chronic obstructive pulmonary disease (COPD) is an age-related condition that has been associated with early telomere attrition; the clinical implications of telomere shortening in COPD are not well known. In this study we aimed to determine the relationship of the epigenetic regulation of telomeric length in peripheral blood with the risk of exacerbations and hospitalization in patients with COPD. Methods: Blood DNA methylation profiles were obtained from 292 patients with COPD enrolled in the placebo arm of the Macrolide Azithromycin to Prevent Rapid Worsening of Symptoms Associated with Chronic Obstructive Pulmonary Disease (MACRO) Study and who were followed for 1-year. We calculated telomere length based on DNA methylation markers (DNAmTL) and related this biomarker to the risk of exacerbation and hospitalization and health status (St. George Respiratory Questionnaire [SGRQ]) score over time using a Cox proportional hazards model. We also used linear models to investigate the associations of DNAmTL with the rates of exacerbation and hospitalization (adjusted for chronological age, lung function, race, sex, smoking, body mass index and cell composition). Results: Participants with short DNAmTL demonstrated increased risk of exacerbation (P = 0.02) and hospitalization (P = 0.03) compared to those with longer DNAmTL. DNAmTL age acceleration was associated with higher rates of exacerbation (P = 1.35 × 10^–04) and hospitalization (P = 5.21 × 10^–03) and poor health status (lower SGRQ scores) independent of chronological age (P = 0.03). Conclusion: Telomeric age based on blood DNA methylation is associated with COPD exacerbation and hospitalization and thus a promising biomarker for poor outcomes in COPD.

Original language	English (US)
Article number	316
Journal	Respiratory research
Volume	22
Issue number	1
DOIs	https://doi.org/10.1186/s12931-021-01911-9
State	Published - Dec 2021

Bibliographical note

Funding Information:
A.I.H.C and S.M. are supported by MITACS and Providence Airway Centre. J.M.L. is supported by the Michael Smith for Health Research Foundation Health Professional Investigator Award and the CIHR/AstraZeneca Early Career Investigator Award. D.D.S. is a Tier 1 Canada Research Chair in COPD and holds the De Lazzari Family Chair at the Centre for Heart Lung Innovation.

Funding Information:
The project was funded by a grant from Genome Canada, CIHR and St. Paul’s Foundation.

Publisher Copyright:
© 2021, The Author(s).

Keywords

AECOPD
COPD
DNA methylation
Epigenetics
Telomeres

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10.1186/s12931-021-01911-9

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Hernández Cordero, A. I., Yang, C. X., Li, X., Milne, S., Chen, V., Hollander, Z., Ng, R., Criner, G. J., Woodruff, P. G., Lazarus, S. C., Connett, J. E., Han, M. L. K., Martinez, F. J., Reed, R. M., Man, S. F. P., Leung, J. M., & Sin, D. D. (2021). Epigenetic marker of telomeric age is associated with exacerbations and hospitalizations in chronic obstructive pulmonary disease. Respiratory research, 22(1), Article 316. https://doi.org/10.1186/s12931-021-01911-9

Hernández Cordero, AI, Yang, CX, Li, X, Milne, S, Chen, V, Hollander, Z, Ng, R, Criner, GJ, Woodruff, PG, Lazarus, SC, Connett, JE, Han, MLK, Martinez, FJ, Reed, RM, Man, SFP, Leung, JM & Sin, DD 2021, 'Epigenetic marker of telomeric age is associated with exacerbations and hospitalizations in chronic obstructive pulmonary disease', Respiratory research, vol. 22, no. 1, 316. https://doi.org/10.1186/s12931-021-01911-9

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title = "Epigenetic marker of telomeric age is associated with exacerbations and hospitalizations in chronic obstructive pulmonary disease",

abstract = "Background: Chronic obstructive pulmonary disease (COPD) is an age-related condition that has been associated with early telomere attrition; the clinical implications of telomere shortening in COPD are not well known. In this study we aimed to determine the relationship of the epigenetic regulation of telomeric length in peripheral blood with the risk of exacerbations and hospitalization in patients with COPD. Methods: Blood DNA methylation profiles were obtained from 292 patients with COPD enrolled in the placebo arm of the Macrolide Azithromycin to Prevent Rapid Worsening of Symptoms Associated with Chronic Obstructive Pulmonary Disease (MACRO) Study and who were followed for 1-year. We calculated telomere length based on DNA methylation markers (DNAmTL) and related this biomarker to the risk of exacerbation and hospitalization and health status (St. George Respiratory Questionnaire [SGRQ]) score over time using a Cox proportional hazards model. We also used linear models to investigate the associations of DNAmTL with the rates of exacerbation and hospitalization (adjusted for chronological age, lung function, race, sex, smoking, body mass index and cell composition). Results: Participants with short DNAmTL demonstrated increased risk of exacerbation (P = 0.02) and hospitalization (P = 0.03) compared to those with longer DNAmTL. DNAmTL age acceleration was associated with higher rates of exacerbation (P = 1.35 × 10–04) and hospitalization (P = 5.21 × 10–03) and poor health status (lower SGRQ scores) independent of chronological age (P = 0.03). Conclusion: Telomeric age based on blood DNA methylation is associated with COPD exacerbation and hospitalization and thus a promising biomarker for poor outcomes in COPD.",

keywords = "AECOPD, COPD, DNA methylation, Epigenetics, Telomeres",

author = "{Hern{\'a}ndez Cordero}, {Ana I.} and Yang, {Chen Xi} and Xuan Li and Stephen Milne and Virginia Chen and Zsuzsanna Hollander and Raymond Ng and Criner, {Gerard J.} and Woodruff, {Prescott G.} and Lazarus, {Stephen C.} and Connett, {John E.} and Han, {Mei Lan K.} and Martinez, {Fernando J.} and Reed, {Robert M.} and Man, {S. F.Paul} and Leung, {Janice M.} and Sin, {Don D.}",

note = "Funding Information: A.I.H.C and S.M. are supported by MITACS and Providence Airway Centre. J.M.L. is supported by the Michael Smith for Health Research Foundation Health Professional Investigator Award and the CIHR/AstraZeneca Early Career Investigator Award. D.D.S. is a Tier 1 Canada Research Chair in COPD and holds the De Lazzari Family Chair at the Centre for Heart Lung Innovation. Funding Information: The project was funded by a grant from Genome Canada, CIHR and St. Paul{\textquoteright}s Foundation. Publisher Copyright: {\textcopyright} 2021, The Author(s).",

year = "2021",

month = dec,

doi = "10.1186/s12931-021-01911-9",

language = "English (US)",

volume = "22",

journal = "Respiratory research",

issn = "1465-9921",

publisher = "BioMed Central",

number = "1",

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TY - JOUR

T1 - Epigenetic marker of telomeric age is associated with exacerbations and hospitalizations in chronic obstructive pulmonary disease

AU - Hernández Cordero, Ana I.

AU - Yang, Chen Xi

AU - Li, Xuan

AU - Milne, Stephen

AU - Chen, Virginia

AU - Hollander, Zsuzsanna

AU - Ng, Raymond

AU - Criner, Gerard J.

AU - Woodruff, Prescott G.

AU - Lazarus, Stephen C.

AU - Connett, John E.

AU - Han, Mei Lan K.

AU - Martinez, Fernando J.

AU - Reed, Robert M.

AU - Man, S. F.Paul

AU - Leung, Janice M.

AU - Sin, Don D.

N1 - Funding Information: A.I.H.C and S.M. are supported by MITACS and Providence Airway Centre. J.M.L. is supported by the Michael Smith for Health Research Foundation Health Professional Investigator Award and the CIHR/AstraZeneca Early Career Investigator Award. D.D.S. is a Tier 1 Canada Research Chair in COPD and holds the De Lazzari Family Chair at the Centre for Heart Lung Innovation. Funding Information: The project was funded by a grant from Genome Canada, CIHR and St. Paul’s Foundation. Publisher Copyright: © 2021, The Author(s).

PY - 2021/12

Y1 - 2021/12

N2 - Background: Chronic obstructive pulmonary disease (COPD) is an age-related condition that has been associated with early telomere attrition; the clinical implications of telomere shortening in COPD are not well known. In this study we aimed to determine the relationship of the epigenetic regulation of telomeric length in peripheral blood with the risk of exacerbations and hospitalization in patients with COPD. Methods: Blood DNA methylation profiles were obtained from 292 patients with COPD enrolled in the placebo arm of the Macrolide Azithromycin to Prevent Rapid Worsening of Symptoms Associated with Chronic Obstructive Pulmonary Disease (MACRO) Study and who were followed for 1-year. We calculated telomere length based on DNA methylation markers (DNAmTL) and related this biomarker to the risk of exacerbation and hospitalization and health status (St. George Respiratory Questionnaire [SGRQ]) score over time using a Cox proportional hazards model. We also used linear models to investigate the associations of DNAmTL with the rates of exacerbation and hospitalization (adjusted for chronological age, lung function, race, sex, smoking, body mass index and cell composition). Results: Participants with short DNAmTL demonstrated increased risk of exacerbation (P = 0.02) and hospitalization (P = 0.03) compared to those with longer DNAmTL. DNAmTL age acceleration was associated with higher rates of exacerbation (P = 1.35 × 10–04) and hospitalization (P = 5.21 × 10–03) and poor health status (lower SGRQ scores) independent of chronological age (P = 0.03). Conclusion: Telomeric age based on blood DNA methylation is associated with COPD exacerbation and hospitalization and thus a promising biomarker for poor outcomes in COPD.

AB - Background: Chronic obstructive pulmonary disease (COPD) is an age-related condition that has been associated with early telomere attrition; the clinical implications of telomere shortening in COPD are not well known. In this study we aimed to determine the relationship of the epigenetic regulation of telomeric length in peripheral blood with the risk of exacerbations and hospitalization in patients with COPD. Methods: Blood DNA methylation profiles were obtained from 292 patients with COPD enrolled in the placebo arm of the Macrolide Azithromycin to Prevent Rapid Worsening of Symptoms Associated with Chronic Obstructive Pulmonary Disease (MACRO) Study and who were followed for 1-year. We calculated telomere length based on DNA methylation markers (DNAmTL) and related this biomarker to the risk of exacerbation and hospitalization and health status (St. George Respiratory Questionnaire [SGRQ]) score over time using a Cox proportional hazards model. We also used linear models to investigate the associations of DNAmTL with the rates of exacerbation and hospitalization (adjusted for chronological age, lung function, race, sex, smoking, body mass index and cell composition). Results: Participants with short DNAmTL demonstrated increased risk of exacerbation (P = 0.02) and hospitalization (P = 0.03) compared to those with longer DNAmTL. DNAmTL age acceleration was associated with higher rates of exacerbation (P = 1.35 × 10–04) and hospitalization (P = 5.21 × 10–03) and poor health status (lower SGRQ scores) independent of chronological age (P = 0.03). Conclusion: Telomeric age based on blood DNA methylation is associated with COPD exacerbation and hospitalization and thus a promising biomarker for poor outcomes in COPD.

KW - AECOPD

KW - COPD

KW - DNA methylation

KW - Epigenetics

KW - Telomeres

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U2 - 10.1186/s12931-021-01911-9

DO - 10.1186/s12931-021-01911-9

M3 - Article

C2 - 34937547

AN - SCOPUS:85121492504

SN - 1465-9921

VL - 22

JO - Respiratory research

JF - Respiratory research

IS - 1

M1 - 316

ER -

Epigenetic marker of telomeric age is associated with exacerbations and hospitalizations in chronic obstructive pulmonary disease

Abstract

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