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 - Kubo, Michiaki
N1 - Funding Information:
Dr Yerges-Armstrong is a current employee stock-owner at GlaxoSmithKline though the current work was completed while an employee of University of Maryland Baltimore. Dr Worrall is a deputy editorship for the journal Neurology and has received National Institutes of Health funding for sample genotyping. Dr Silverman has received honoraria from Novartis for Continuing Medical Education Seminars and grant and travel support from GlaxoSmithKline. Helena Kuivaniemi has received funding from the National Institutes of Health National Heart, Lung, and Blood Institute (HL064310, HL044682), the Pennsylvania Commonwealth Universal Research Enhancement program, the Geisinger Clinical Research Fund, the American Heart Association, the Ben Franklin Technology Development Fund of Pennsylvania, and the National Institutes of Health for sample genotyping (U01HG006382). Dr Eeles has received honoraria from the Genitourinary Cancers Symposium organised by American Society of Clinical Oncology. Dr Rotter has received funding from the National Institutes of Health (R01HL105756), the National Center for Advancing Translational Sciences, CTSI grant UL1TR001881, and the National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center grant DK063491 to the Southern California Diabetes Research Center. No other conflicts reported. This work was supported by CRUK grant number C18281/A19169 (the Integrative Cancer Epidemiology Programme). Dr Haycock is supported by CRUK Population Research Postdoctoral Fellowship C52724/A20138. The MRC Integrative Epidemiology Unit is supported by grants MC-UU-12013/1 and MC-UU-12013/2. Dr Martin is supported by the National Institute for Health Research (NIHR), the Bristol Nutritional Biomedical Research Unit and the University of Bristol. Dr Timpson is supported by Medical Research Council MC-UU-12013/3.
Publisher Copyright:
Copyright 2017 American Medical Association. All rights reserved.
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.
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U2 - 10.1001/jamaoncol.2016.5945
DO - 10.1001/jamaoncol.2016.5945
M3 - Article
C2 - 28241208
AN - SCOPUS:85019502119
VL - 3
SP - 636
EP - 651
JO - JAMA oncology
JF - JAMA oncology
SN - 2374-2437
IS - 5
ER -