Telomere length and risk of idiopathic pulmonary fibrosis and chronic obstructive pulmonary disease: a mendelian randomisation study

Anna Duckworth; Michael A. Gibbons; Richard J. Allen; Howard Almond; Robin N. Beaumont; Andrew R. Wood; Katie Lunnon; Mark A. Lindsay; Louise V. Wain; Jess Tyrrell; Chris J. Scotton

doi:10.1016/S2213-2600(20)30364-7

Telomere length and risk of idiopathic pulmonary fibrosis and chronic obstructive pulmonary disease: a mendelian randomisation study

Anna Duckworth, Michael A. Gibbons, Richard J. Allen, Howard Almond, Robin N. Beaumont, Andrew R. Wood, Katie Lunnon, Mark A. Lindsay, Louise V. Wain, Jess Tyrrell, Chris J. Scotton

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Abstract

Background: Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease accounting for 1% of UK deaths. In the familial form of pulmonary fibrosis, causal genes have been identified in about 30% of cases, and a majority of these causal genes are associated with telomere maintenance. Prematurely shortened leukocyte telomere length is associated with IPF and chronic obstructive pulmonary disease (COPD), a disease with similar demographics and shared risk factors. Using mendelian randomisation, we investigated evidence supporting a causal role for short telomeres in IPF and COPD. Methods: Mendelian randomisation inference of telomere length causality was done for IPF (up to 1369 cases) and COPD (13 538 cases) against 435 866 controls of European ancestry in UK Biobank. Polygenic risk scores were calculated and two-sample mendelian randomisation analyses were done using seven genetic variants previously associated with telomere length, with replication analysis in an IPF cohort (2668 cases vs 8591 controls) and COPD cohort (15 256 cases vs 47 936 controls). Findings: In the UK Biobank, a genetically instrumented one-SD shorter telomere length was associated with higher odds of IPF (odds ratio [OR] 4·19, 95% CI 2·33–7·55; p=0·0031) but not COPD (1·07, 0·88–1·30; p=0·51). Similarly, an association was found in the IPF replication cohort (12·3, 5·05–30·1; p=0·0015) and not in the COPD replication cohort (1·04, 0·71–1·53; p=0·83). Meta-analysis of the two-sample mendelian randomisation results provided evidence inferring that shorter telomeres cause IPF (5·81 higher odds of IPF, 95% CI 3·56–9·50; p=2·19 × 10⁻¹²). There was no evidence to infer that telomere length caused COPD (OR 1·07, 95% CI 0·90–1·27; p=0·46). Interpretation: Cellular senescence is hypothesised as a major driving force in IPF and COPD; telomere shortening might be a contributory factor in IPF, suggesting divergent mechanisms in COPD. Defining a key role for telomere shortening enables greater focus in telomere-related diagnostics, treatments, and the search for a cure in IPF. Investigation of therapies that improve telomere length is warranted. Funding: Medical Research Council.

Original language	English
Article number	0
Pages (from-to)	1-0
Number of pages	0
Journal	The Lancet Respiratory Medicine
Volume	0
Issue number	0
Early online date	13 Nov 2020
DOIs	https://doi.org/10.1016/S2213-2600(20)30364-7
Publication status	Published - 13 Nov 2020

Bibliographical note

Funding Information:
AD is funded by the GW4 BioMed Medical Research Doctoral Training Partnership. JT is supported by an Academy of Medical Sciences Springboard award, which is supported by the Academy of Medical Sciences, Wellcome, Global Challenges Research Fund, the Government Department of Business, Energy and Industrial strategy, the British Heart Foundation, and Diabetes UK (SBF004\1079). RJA is an Action for Pulmonary Fibrosis Research Fellow. LVW holds a GlaxoSmithKline and British Lung Foundation Chair in Respiratory Research. This research has been done using the UK Biobank Resource (applications 9072 and 44046). The authors would like to acknowledge the use of the University of Exeter High-Performance Computing facility in carrying out this work. The Research was partially supported by the National Institute for Health Research (NIHR) Leicester Biomedical Research Centre; the views expressed are those of the author(s) and not necessarily those of the National Health Service, the NIHR, or the Department of Health.

Publisher Copyright:
© 2020 Elsevier Ltd

Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.

Funding

AD is funded by the GW4 BioMed Medical Research Doctoral Training Partnership. JT is supported by an Academy of Medical Sciences Springboard award, which is supported by the Academy of Medical Sciences, Wellcome, Global Challenges Research Fund, the Government Department of Business, Energy and Industrial strategy, the British Heart Foundation, and Diabetes UK (SBF004\1079). RJA is an Action for Pulmonary Fibrosis Research Fellow. LVW holds a GlaxoSmithKline and British Lung Foundation Chair in Respiratory Research. This research has been done using the UK Biobank Resource (applications 9072 and 44046). The authors would like to acknowledge the use of the University of Exeter High-Performance Computing facility in carrying out this work. The Research was partially supported by the National Institute for Health Research (NIHR) Leicester Biomedical Research Centre; the views expressed are those of the author(s) and not necessarily those of the National Health Service, the NIHR, or the Department of Health.

ASJC Scopus subject areas

Pulmonary and Respiratory Medicine

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10.1016/S2213-2600(20)30364-7

LRM Manuscript version IN PRESS for SymplecticAccepted author manuscript, 564 KBLicence: Unspecified

https://ore.exeter.ac.uk/repository/handle/10871/123867

Cite this

Duckworth, A., Gibbons, M. A., Allen, R. J., Almond, H., Beaumont, R. N., Wood, A. R., Lunnon, K., Lindsay, M. A., Wain, L. V., Tyrrell, J., & Scotton, C. J. (2020). Telomere length and risk of idiopathic pulmonary fibrosis and chronic obstructive pulmonary disease: a mendelian randomisation study. The Lancet Respiratory Medicine, 0(0), 1-0. Article 0. https://doi.org/10.1016/S2213-2600(20)30364-7

Duckworth, A, Gibbons, MA, Allen, RJ, Almond, H, Beaumont, RN, Wood, AR, Lunnon, K, Lindsay, MA, Wain, LV, Tyrrell, J & Scotton, CJ 2020, 'Telomere length and risk of idiopathic pulmonary fibrosis and chronic obstructive pulmonary disease: a mendelian randomisation study', The Lancet Respiratory Medicine, vol. 0, no. 0, 0, pp. 1-0. https://doi.org/10.1016/S2213-2600(20)30364-7

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title = "Telomere length and risk of idiopathic pulmonary fibrosis and chronic obstructive pulmonary disease: a mendelian randomisation study",

abstract = "Background: Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease accounting for 1% of UK deaths. In the familial form of pulmonary fibrosis, causal genes have been identified in about 30% of cases, and a majority of these causal genes are associated with telomere maintenance. Prematurely shortened leukocyte telomere length is associated with IPF and chronic obstructive pulmonary disease (COPD), a disease with similar demographics and shared risk factors. Using mendelian randomisation, we investigated evidence supporting a causal role for short telomeres in IPF and COPD. Methods: Mendelian randomisation inference of telomere length causality was done for IPF (up to 1369 cases) and COPD (13 538 cases) against 435 866 controls of European ancestry in UK Biobank. Polygenic risk scores were calculated and two-sample mendelian randomisation analyses were done using seven genetic variants previously associated with telomere length, with replication analysis in an IPF cohort (2668 cases vs 8591 controls) and COPD cohort (15 256 cases vs 47 936 controls). Findings: In the UK Biobank, a genetically instrumented one-SD shorter telomere length was associated with higher odds of IPF (odds ratio [OR] 4·19, 95% CI 2·33–7·55; p=0·0031) but not COPD (1·07, 0·88–1·30; p=0·51). Similarly, an association was found in the IPF replication cohort (12·3, 5·05–30·1; p=0·0015) and not in the COPD replication cohort (1·04, 0·71–1·53; p=0·83). Meta-analysis of the two-sample mendelian randomisation results provided evidence inferring that shorter telomeres cause IPF (5·81 higher odds of IPF, 95% CI 3·56–9·50; p=2·19 × 10−12). There was no evidence to infer that telomere length caused COPD (OR 1·07, 95% CI 0·90–1·27; p=0·46). Interpretation: Cellular senescence is hypothesised as a major driving force in IPF and COPD; telomere shortening might be a contributory factor in IPF, suggesting divergent mechanisms in COPD. Defining a key role for telomere shortening enables greater focus in telomere-related diagnostics, treatments, and the search for a cure in IPF. Investigation of therapies that improve telomere length is warranted. Funding: Medical Research Council.",

author = "Anna Duckworth and Gibbons, {Michael A.} and Allen, {Richard J.} and Howard Almond and Beaumont, {Robin N.} and Wood, {Andrew R.} and Katie Lunnon and Lindsay, {Mark A.} and Wain, {Louise V.} and Jess Tyrrell and Scotton, {Chris J.}",

note = "Funding Information: AD is funded by the GW4 BioMed Medical Research Doctoral Training Partnership. JT is supported by an Academy of Medical Sciences Springboard award, which is supported by the Academy of Medical Sciences, Wellcome, Global Challenges Research Fund, the Government Department of Business, Energy and Industrial strategy, the British Heart Foundation, and Diabetes UK (SBF004\1079). RJA is an Action for Pulmonary Fibrosis Research Fellow. LVW holds a GlaxoSmithKline and British Lung Foundation Chair in Respiratory Research. This research has been done using the UK Biobank Resource (applications 9072 and 44046). The authors would like to acknowledge the use of the University of Exeter High-Performance Computing facility in carrying out this work. The Research was partially supported by the National Institute for Health Research (NIHR) Leicester Biomedical Research Centre; the views expressed are those of the author(s) and not necessarily those of the National Health Service, the NIHR, or the Department of Health. Publisher Copyright: {\textcopyright} 2020 Elsevier Ltd Copyright: Copyright 2020 Elsevier B.V., All rights reserved.",

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doi = "10.1016/S2213-2600(20)30364-7",

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TY - JOUR

T1 - Telomere length and risk of idiopathic pulmonary fibrosis and chronic obstructive pulmonary disease

T2 - a mendelian randomisation study

AU - Duckworth, Anna

AU - Gibbons, Michael A.

AU - Allen, Richard J.

AU - Almond, Howard

AU - Beaumont, Robin N.

AU - Wood, Andrew R.

AU - Lunnon, Katie

AU - Lindsay, Mark A.

AU - Wain, Louise V.

AU - Tyrrell, Jess

AU - Scotton, Chris J.

N1 - Funding Information: AD is funded by the GW4 BioMed Medical Research Doctoral Training Partnership. JT is supported by an Academy of Medical Sciences Springboard award, which is supported by the Academy of Medical Sciences, Wellcome, Global Challenges Research Fund, the Government Department of Business, Energy and Industrial strategy, the British Heart Foundation, and Diabetes UK (SBF004\1079). RJA is an Action for Pulmonary Fibrosis Research Fellow. LVW holds a GlaxoSmithKline and British Lung Foundation Chair in Respiratory Research. This research has been done using the UK Biobank Resource (applications 9072 and 44046). The authors would like to acknowledge the use of the University of Exeter High-Performance Computing facility in carrying out this work. The Research was partially supported by the National Institute for Health Research (NIHR) Leicester Biomedical Research Centre; the views expressed are those of the author(s) and not necessarily those of the National Health Service, the NIHR, or the Department of Health. Publisher Copyright: © 2020 Elsevier Ltd Copyright: Copyright 2020 Elsevier B.V., All rights reserved.

PY - 2020/11/13

Y1 - 2020/11/13

N2 - Background: Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease accounting for 1% of UK deaths. In the familial form of pulmonary fibrosis, causal genes have been identified in about 30% of cases, and a majority of these causal genes are associated with telomere maintenance. Prematurely shortened leukocyte telomere length is associated with IPF and chronic obstructive pulmonary disease (COPD), a disease with similar demographics and shared risk factors. Using mendelian randomisation, we investigated evidence supporting a causal role for short telomeres in IPF and COPD. Methods: Mendelian randomisation inference of telomere length causality was done for IPF (up to 1369 cases) and COPD (13 538 cases) against 435 866 controls of European ancestry in UK Biobank. Polygenic risk scores were calculated and two-sample mendelian randomisation analyses were done using seven genetic variants previously associated with telomere length, with replication analysis in an IPF cohort (2668 cases vs 8591 controls) and COPD cohort (15 256 cases vs 47 936 controls). Findings: In the UK Biobank, a genetically instrumented one-SD shorter telomere length was associated with higher odds of IPF (odds ratio [OR] 4·19, 95% CI 2·33–7·55; p=0·0031) but not COPD (1·07, 0·88–1·30; p=0·51). Similarly, an association was found in the IPF replication cohort (12·3, 5·05–30·1; p=0·0015) and not in the COPD replication cohort (1·04, 0·71–1·53; p=0·83). Meta-analysis of the two-sample mendelian randomisation results provided evidence inferring that shorter telomeres cause IPF (5·81 higher odds of IPF, 95% CI 3·56–9·50; p=2·19 × 10−12). There was no evidence to infer that telomere length caused COPD (OR 1·07, 95% CI 0·90–1·27; p=0·46). Interpretation: Cellular senescence is hypothesised as a major driving force in IPF and COPD; telomere shortening might be a contributory factor in IPF, suggesting divergent mechanisms in COPD. Defining a key role for telomere shortening enables greater focus in telomere-related diagnostics, treatments, and the search for a cure in IPF. Investigation of therapies that improve telomere length is warranted. Funding: Medical Research Council.

AB - Background: Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease accounting for 1% of UK deaths. In the familial form of pulmonary fibrosis, causal genes have been identified in about 30% of cases, and a majority of these causal genes are associated with telomere maintenance. Prematurely shortened leukocyte telomere length is associated with IPF and chronic obstructive pulmonary disease (COPD), a disease with similar demographics and shared risk factors. Using mendelian randomisation, we investigated evidence supporting a causal role for short telomeres in IPF and COPD. Methods: Mendelian randomisation inference of telomere length causality was done for IPF (up to 1369 cases) and COPD (13 538 cases) against 435 866 controls of European ancestry in UK Biobank. Polygenic risk scores were calculated and two-sample mendelian randomisation analyses were done using seven genetic variants previously associated with telomere length, with replication analysis in an IPF cohort (2668 cases vs 8591 controls) and COPD cohort (15 256 cases vs 47 936 controls). Findings: In the UK Biobank, a genetically instrumented one-SD shorter telomere length was associated with higher odds of IPF (odds ratio [OR] 4·19, 95% CI 2·33–7·55; p=0·0031) but not COPD (1·07, 0·88–1·30; p=0·51). Similarly, an association was found in the IPF replication cohort (12·3, 5·05–30·1; p=0·0015) and not in the COPD replication cohort (1·04, 0·71–1·53; p=0·83). Meta-analysis of the two-sample mendelian randomisation results provided evidence inferring that shorter telomeres cause IPF (5·81 higher odds of IPF, 95% CI 3·56–9·50; p=2·19 × 10−12). There was no evidence to infer that telomere length caused COPD (OR 1·07, 95% CI 0·90–1·27; p=0·46). Interpretation: Cellular senescence is hypothesised as a major driving force in IPF and COPD; telomere shortening might be a contributory factor in IPF, suggesting divergent mechanisms in COPD. Defining a key role for telomere shortening enables greater focus in telomere-related diagnostics, treatments, and the search for a cure in IPF. Investigation of therapies that improve telomere length is warranted. Funding: Medical Research Council.

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Telomere length and risk of idiopathic pulmonary fibrosis and chronic obstructive pulmonary disease: a mendelian randomisation study

Abstract

Bibliographical note

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Mark Lindsay

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Telomere length and risk of idiopathic pulmonary fibrosis and chronic obstructive pulmonary disease: a mendelian randomisation study

Abstract

Bibliographical note

Funding

ASJC Scopus subject areas

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Fingerprint

Profiles

Mark Lindsay

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