Association between telomere length and risk of cancer and non-neoplastic diseases a mendelian randomization study

Telomeres Mendelian Randomization Collaboration

doi:10.1001/jamaoncol.2016.5945

Association between telomere length and risk of cancer and non-neoplastic diseases a mendelian randomization study

Telomeres Mendelian Randomization Collaboration

University of Bristol
University of Cambridge
University of Queensland
Innsbruck Medical University
Rutgers New Jersey Medical School
King's College London
Guy's and St Thomas' NHS Foundation Trust
Royal Marsden NHS Foundation Trust
University of Texas MD Anderson Cancer Center
Queensland Institute of Medical Research
University of Leeds
Boston University
University of Virginia
University of Toronto
Dartmouth College
Dana-Farber Cancer Institute
National Institutes of Health
Helenic Health Foundation
National and Kapodistrian University of Athens
Utrecht University
University of Tromsø – The Arctic University of Norway
Institute Catala Oncologia
German Cancer Research Center
Université Paris-Saclay
Institut Gustave Roussy
Human Genetics Foundation (HuGeF)
University of Melbourne
Aarhus University
Imperial College London
Azienda Ospedaliera Civile M.P. Arezzo
Umeå University
University of Otago
University of Leicester
University of Edinburgh
Stellenbosch University
Geisinger Medical Center
International Agency for Research on Cancer
University of California at San Francisco
Memorial Sloan-Kettering Cancer Center
Mayo Clinic College of Medicine and Science
Yale University
Johns Hopkins University
Indiana University-Purdue University Indianapolis
Indiana University Bloomington
University of Pennsylvania
Radboud University Nijmegen
Netherlands Comprehensive Cancer Organization
Queen Mary University of London
Institute of Cancer Research
Helmholtz Zentrum München - German Research Center for Environmental Health
University of Michigan, Ann Arbor
Georgetown University
University of Freiburg
University of Verona
RIKEN
University of Oxford
Queensland University of Technology
University of Washington
University of Cincinnati
Massachusetts General Hospital
Wake Forest University
Brigham and Women’s Hospital
University of Colorado Anschutz Medical Campus
Sir Charles Gairdner Hospital
PathWest Laboratory Medicine WA
University of Western Australia
University of Texas Health Science Center at Houston
Erasmus University Rotterdam
Columbia University
University of Bonn
Anhui Medical University
University of Chinese Academy of Sciences
National Jewish Health
University of California at Los Angeles
Charité – Universitätsmedizin Berlin
University of Lübeck
Peking University
Stanford University
Vanderbilt University
Friedrich-Alexander University Erlangen-Nürnberg
Shonan Kamakura General Hospital
The University of Tokyo
Teikyo Heisei University
Agency for Science, Technology and Research, Singapore
Sun Yat-Sen University Cancer Center
Chinese Academy of Medical Sciences
Lund University
University of Pisa
University Hospital of Schleswig-Holstein
Kiel University
Hospital Universitario Nuestra Senora de Candelaria
Centro de Investigacion Biomedica en Red Enfermedades Respiratorias (CIBERES)
The University of Chicago
Sungkyunkwan University
INSERM U1052
INSERM U830
University of Alabama at Birmingham
The University of Hong Kong
Chang Gung Memorial Hospital
Chang Gung University
Flinders University
Soongsil University
Heidelberg University
Kobe University
National Heart Lung and Blood Institute’s and Boston University’s Framingham Heart Study
Weill Cornell Medicine-Qatar
Wellcome Trust Sanger Institute
University of Maryland, Baltimore
Singapore National Eye Center
National University of Singapore
Duke-NUS Medical School
Capital Medical University

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

435 Citations (Scopus)

Abstract

IMPORTANCE: The causal direction and magnitude of the association between telomere length and incidence of cancer and non-neoplastic diseases is uncertain owing to the susceptibility of observational studies to confounding and reverse causation. OBJECTIVE: To conduct a Mendelian randomization study, using germline genetic variants as instrumental variables, to appraise the causal relevance of telomere length for risk of cancer and non-neoplastic diseases. DATA SOURCES: Genomewide association studies (GWAS) published up to January 15, 2015. STUDY SELECTION: GWAS of noncommunicable diseases that assayed germline genetic variation and did not select cohort or control participants on the basis of preexisting diseases. Of 163 GWAS of noncommunicable diseases identified, summary data from 103 were available. DATA EXTRACTION AND SYNTHESIS: Summary association statistics for single nucleotide polymorphisms (SNPs) that are strongly associated with telomere length in the general population. MAIN OUTCOMES AND MEASURES: Odds ratios (ORs) and 95% confidence intervals (CIs) for disease per standard deviation (SD) higher telomere length due to germline genetic variation. RESULTS: Summary data were available for 35 cancers and 48 non-neoplastic diseases, corresponding to 420 081 cases (median cases, 2526 per disease) and 1 093 105 controls (median, 6789 per disease). Increased telomere length due to germline genetic variation was generally associated with increased risk for site-specific cancers. The strongest associations (ORs [95% CIs] per 1-SD change in genetically increased telomere length) were observed for glioma, 5.27 (3.15-8.81); serous low-malignant-potential ovarian cancer, 4.35 (2.39-7.94); lung adenocarcinoma, 3.19 (2.40-4.22); neuroblastoma, 2.98 (1.92-4.62); bladder cancer, 2.19 (1.32-3.66); melanoma, 1.87 (1.55-2.26); testicular cancer, 1.76 (1.02-3.04); kidney cancer, 1.55 (1.08-2.23); and endometrial cancer, 1.31 (1.07-1.61). Associations were stronger for rarer cancers and at tissue sites with lower rates of stem cell division. There was generally little evidence of association between genetically increased telomere length and risk of psychiatric, autoimmune, inflammatory, diabetic, and other non-neoplastic diseases, except for coronary heart disease (OR, 0.78 [95% CI, 0.67-0.90]), abdominal aortic aneurysm (OR, 0.63 [95% CI, 0.49-0.81]), celiac disease (OR, 0.42 [95% CI, 0.28-0.61]) and interstitial lung disease (OR, 0.09 [95% CI, 0.05-0.15]). CONCLUSIONS AND RELEVANCE: It is likely that longer telomeres increase risk for several cancers but reduce risk for some non-neoplastic diseases, including cardiovascular diseases.

Original language	English
Pages (from-to)	636-651
Number of pages	16
Journal	JAMA Oncology
Volume	3
Issue number	5
DOIs	https://doi.org/10.1001/jamaoncol.2016.5945
Publication status	Published - 1 May 2017

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10.1001/jamaoncol.2016.5945

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@article{9407d203b9f840dfb7b7169c037b6a08,

title = "Association between telomere length and risk of cancer and non-neoplastic diseases a mendelian randomization study",

abstract = "IMPORTANCE: The causal direction and magnitude of the association between telomere length and incidence of cancer and non-neoplastic diseases is uncertain owing to the susceptibility of observational studies to confounding and reverse causation. OBJECTIVE: To conduct a Mendelian randomization study, using germline genetic variants as instrumental variables, to appraise the causal relevance of telomere length for risk of cancer and non-neoplastic diseases. DATA SOURCES: Genomewide association studies (GWAS) published up to January 15, 2015. STUDY SELECTION: GWAS of noncommunicable diseases that assayed germline genetic variation and did not select cohort or control participants on the basis of preexisting diseases. Of 163 GWAS of noncommunicable diseases identified, summary data from 103 were available. DATA EXTRACTION AND SYNTHESIS: Summary association statistics for single nucleotide polymorphisms (SNPs) that are strongly associated with telomere length in the general population. MAIN OUTCOMES AND MEASURES: Odds ratios (ORs) and 95\% confidence intervals (CIs) for disease per standard deviation (SD) higher telomere length due to germline genetic variation. RESULTS: Summary data were available for 35 cancers and 48 non-neoplastic diseases, corresponding to 420 081 cases (median cases, 2526 per disease) and 1 093 105 controls (median, 6789 per disease). Increased telomere length due to germline genetic variation was generally associated with increased risk for site-specific cancers. The strongest associations (ORs [95\% CIs] per 1-SD change in genetically increased telomere length) were observed for glioma, 5.27 (3.15-8.81); serous low-malignant-potential ovarian cancer, 4.35 (2.39-7.94); lung adenocarcinoma, 3.19 (2.40-4.22); neuroblastoma, 2.98 (1.92-4.62); bladder cancer, 2.19 (1.32-3.66); melanoma, 1.87 (1.55-2.26); testicular cancer, 1.76 (1.02-3.04); kidney cancer, 1.55 (1.08-2.23); and endometrial cancer, 1.31 (1.07-1.61). Associations were stronger for rarer cancers and at tissue sites with lower rates of stem cell division. There was generally little evidence of association between genetically increased telomere length and risk of psychiatric, autoimmune, inflammatory, diabetic, and other non-neoplastic diseases, except for coronary heart disease (OR, 0.78 [95\% CI, 0.67-0.90]), abdominal aortic aneurysm (OR, 0.63 [95\% CI, 0.49-0.81]), celiac disease (OR, 0.42 [95\% CI, 0.28-0.61]) and interstitial lung disease (OR, 0.09 [95\% CI, 0.05-0.15]). CONCLUSIONS AND RELEVANCE: It is likely that longer telomeres increase risk for several cancers but reduce risk for some non-neoplastic diseases, including cardiovascular diseases.",

author = "\{Telomeres Mendelian Randomization Collaboration\} and Haycock, \{Philip C.\} and Stephen Burgess and Aayah Nounu and Jie Zheng and Okoli, \{George N.\} and Jack Bowden and Wade, \{Kaitlin Hazel\} and Timpson, \{Nicholas J.\} and Evans, \{David M.\} and Peter Willeit and Abraham Aviv and Gaunt, \{Tom R.\} and Gibran Hemani and Massimo Mangino and Ellis, \{Hayley Patricia\} and Kurian, \{Kathreena M.\} and Pooley, \{Karen A.\} and Eeles, \{Rosalind A.\} and Lee, \{Jeffrey E.\} and Shenying Fang and Chen, \{Wei V.\} and Law, \{Matthew H.\} and Bowdler, \{Lisa M.\} and Iles, \{Mark M.\} and Qiong Yang and Worrall, \{Bradford B.\} and Markus, \{Hugh Stephen\} and Hung, \{Rayjean J.\} and Amos, \{Chris I.\} and Spurdle, \{Amanda B.\} and Thompson, \{Deborah J.\} and O'Mara, \{Tracy A.\} and Brian Wolpin and Laufey Amundadottir and Rachael Stolzenberg-Solomon and Antonia Trichopoulou and Onland-Moret, \{N. Charlotte\} and Eiliv Lund and Duell, \{Eric J.\} and Federico Canzian and Gianluca Severi and Kim Overvad and Gunter, \{Marc J.\} and Rosario Tumino and Ulrika Svenson and \{Van Rij\}, Andre and Baas, \{Annette F.\} and Bown, \{Matthew J.\} and Samani, \{Nilesh J.\} and Omar Albagha",

year = "2017",

month = may,

day = "1",

doi = "10.1001/jamaoncol.2016.5945",

language = "English",

volume = "3",

pages = "636--651",

journal = "JAMA Oncology",

issn = "2374-2437",

publisher = "American Medical Association",

number = "5",

}

TY - JOUR

T1 - Association between telomere length and risk of cancer and non-neoplastic diseases a mendelian randomization study

AU - Telomeres Mendelian Randomization Collaboration

AU - Haycock, Philip C.

AU - Burgess, Stephen

AU - Nounu, Aayah

AU - Zheng, Jie

AU - Okoli, George N.

AU - Bowden, Jack

AU - Wade, Kaitlin Hazel

AU - Timpson, Nicholas J.

AU - Evans, David M.

AU - Willeit, Peter

AU - Aviv, Abraham

AU - Gaunt, Tom R.

AU - Hemani, Gibran

AU - Mangino, Massimo

AU - Ellis, Hayley Patricia

AU - Kurian, Kathreena M.

AU - Pooley, Karen A.

AU - Eeles, Rosalind A.

AU - Lee, Jeffrey E.

AU - Fang, Shenying

AU - Chen, Wei V.

AU - Law, Matthew H.

AU - Bowdler, Lisa M.

AU - Iles, Mark M.

AU - Yang, Qiong

AU - Worrall, Bradford B.

AU - Markus, Hugh Stephen

AU - Hung, Rayjean J.

AU - Amos, Chris I.

AU - Spurdle, Amanda B.

AU - Thompson, Deborah J.

AU - O'Mara, Tracy A.

AU - Wolpin, Brian

AU - Amundadottir, Laufey

AU - Stolzenberg-Solomon, Rachael

AU - Trichopoulou, Antonia

AU - Onland-Moret, N. Charlotte

AU - Lund, Eiliv

AU - Duell, Eric J.

AU - Canzian, Federico

AU - Severi, Gianluca

AU - Overvad, Kim

AU - Gunter, Marc J.

AU - Tumino, Rosario

AU - Svenson, Ulrika

AU - Van Rij, Andre

AU - Baas, Annette F.

AU - Bown, Matthew J.

AU - Samani, Nilesh J.

AU - Albagha, Omar

PY - 2017/5/1

Y1 - 2017/5/1

N2 - IMPORTANCE: The causal direction and magnitude of the association between telomere length and incidence of cancer and non-neoplastic diseases is uncertain owing to the susceptibility of observational studies to confounding and reverse causation. OBJECTIVE: To conduct a Mendelian randomization study, using germline genetic variants as instrumental variables, to appraise the causal relevance of telomere length for risk of cancer and non-neoplastic diseases. DATA SOURCES: Genomewide association studies (GWAS) published up to January 15, 2015. STUDY SELECTION: GWAS of noncommunicable diseases that assayed germline genetic variation and did not select cohort or control participants on the basis of preexisting diseases. Of 163 GWAS of noncommunicable diseases identified, summary data from 103 were available. DATA EXTRACTION AND SYNTHESIS: Summary association statistics for single nucleotide polymorphisms (SNPs) that are strongly associated with telomere length in the general population. MAIN OUTCOMES AND MEASURES: Odds ratios (ORs) and 95% confidence intervals (CIs) for disease per standard deviation (SD) higher telomere length due to germline genetic variation. RESULTS: Summary data were available for 35 cancers and 48 non-neoplastic diseases, corresponding to 420 081 cases (median cases, 2526 per disease) and 1 093 105 controls (median, 6789 per disease). Increased telomere length due to germline genetic variation was generally associated with increased risk for site-specific cancers. The strongest associations (ORs [95% CIs] per 1-SD change in genetically increased telomere length) were observed for glioma, 5.27 (3.15-8.81); serous low-malignant-potential ovarian cancer, 4.35 (2.39-7.94); lung adenocarcinoma, 3.19 (2.40-4.22); neuroblastoma, 2.98 (1.92-4.62); bladder cancer, 2.19 (1.32-3.66); melanoma, 1.87 (1.55-2.26); testicular cancer, 1.76 (1.02-3.04); kidney cancer, 1.55 (1.08-2.23); and endometrial cancer, 1.31 (1.07-1.61). Associations were stronger for rarer cancers and at tissue sites with lower rates of stem cell division. There was generally little evidence of association between genetically increased telomere length and risk of psychiatric, autoimmune, inflammatory, diabetic, and other non-neoplastic diseases, except for coronary heart disease (OR, 0.78 [95% CI, 0.67-0.90]), abdominal aortic aneurysm (OR, 0.63 [95% CI, 0.49-0.81]), celiac disease (OR, 0.42 [95% CI, 0.28-0.61]) and interstitial lung disease (OR, 0.09 [95% CI, 0.05-0.15]). CONCLUSIONS AND RELEVANCE: It is likely that longer telomeres increase risk for several cancers but reduce risk for some non-neoplastic diseases, including cardiovascular diseases.

AB - IMPORTANCE: The causal direction and magnitude of the association between telomere length and incidence of cancer and non-neoplastic diseases is uncertain owing to the susceptibility of observational studies to confounding and reverse causation. OBJECTIVE: To conduct a Mendelian randomization study, using germline genetic variants as instrumental variables, to appraise the causal relevance of telomere length for risk of cancer and non-neoplastic diseases. DATA SOURCES: Genomewide association studies (GWAS) published up to January 15, 2015. STUDY SELECTION: GWAS of noncommunicable diseases that assayed germline genetic variation and did not select cohort or control participants on the basis of preexisting diseases. Of 163 GWAS of noncommunicable diseases identified, summary data from 103 were available. DATA EXTRACTION AND SYNTHESIS: Summary association statistics for single nucleotide polymorphisms (SNPs) that are strongly associated with telomere length in the general population. MAIN OUTCOMES AND MEASURES: Odds ratios (ORs) and 95% confidence intervals (CIs) for disease per standard deviation (SD) higher telomere length due to germline genetic variation. RESULTS: Summary data were available for 35 cancers and 48 non-neoplastic diseases, corresponding to 420 081 cases (median cases, 2526 per disease) and 1 093 105 controls (median, 6789 per disease). Increased telomere length due to germline genetic variation was generally associated with increased risk for site-specific cancers. The strongest associations (ORs [95% CIs] per 1-SD change in genetically increased telomere length) were observed for glioma, 5.27 (3.15-8.81); serous low-malignant-potential ovarian cancer, 4.35 (2.39-7.94); lung adenocarcinoma, 3.19 (2.40-4.22); neuroblastoma, 2.98 (1.92-4.62); bladder cancer, 2.19 (1.32-3.66); melanoma, 1.87 (1.55-2.26); testicular cancer, 1.76 (1.02-3.04); kidney cancer, 1.55 (1.08-2.23); and endometrial cancer, 1.31 (1.07-1.61). Associations were stronger for rarer cancers and at tissue sites with lower rates of stem cell division. There was generally little evidence of association between genetically increased telomere length and risk of psychiatric, autoimmune, inflammatory, diabetic, and other non-neoplastic diseases, except for coronary heart disease (OR, 0.78 [95% CI, 0.67-0.90]), abdominal aortic aneurysm (OR, 0.63 [95% CI, 0.49-0.81]), celiac disease (OR, 0.42 [95% CI, 0.28-0.61]) and interstitial lung disease (OR, 0.09 [95% CI, 0.05-0.15]). CONCLUSIONS AND RELEVANCE: It is likely that longer telomeres increase risk for several cancers but reduce risk for some non-neoplastic diseases, including cardiovascular diseases.

UR - https://www.scopus.com/pages/publications/85019502119

U2 - 10.1001/jamaoncol.2016.5945

DO - 10.1001/jamaoncol.2016.5945

M3 - Article

C2 - 28241208

AN - SCOPUS:85019502119

SN - 2374-2437

VL - 3

SP - 636

EP - 651

JO - JAMA Oncology

JF - JAMA Oncology

IS - 5

ER -

Association between telomere length and risk of cancer and non-neoplastic diseases a mendelian randomization study

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