Association Between Telomere Length and Risk of Cancer and Non-Neoplastic Diseases: A Mendelian Randomization Study

Haycock PC, Burgess S, Nounu A, Zheng J, Okoli GN, Bowden J, Wade KH, Timpson NJ, Evans DM, Willeit P, Aviv A, Gaunt T, Hemani G, Mangino M, Ellis HP, Kurian KM, Pooley KA, Eeles RA, Lee JE, Fang S, Chen WV, Law MH, Bowdler LM, Iles MM, Yang Q, Worrall BB, Markus HS, Hung RJ, Amos CI, Spurdle AB, Thompson DJ, O'Mara TA, Wolpin B, Amundadottir L, Stolzenberg-Solomon R, Trichopoulou A, Onland-Moret C, Lund E, Duell EJ, Canzian F, Severi G, Overvad K, Gunter MJ, Tumino R, Svenson U, Van Rij A, Baas AF, Bown MJ, Samani NJ, Van T'Hof FNG, Tromp G, Jones GT, Kuivaniemi H, Elmore JR, Johansson M, Mckay J, Scelo G, Carreras-Torres R, Gaborieau V, Brennan P, Bracci PM, Neale RE, Olson SH, Gallinger S, Li D, Petersen GM, Risch HA, Klein AP, Han J, Abnet CC, Freedman ND, Taylor PR, Maris JM, Aben KK, Kiemeney LA, Vermeulen SH, Wiencke JK, Walsh KM, Wrensch M, Rice T, Turnbull C, Litchfield K, Paternoster L, Standl M, Abecasis GR, Sangiovanni JP, Li Y, Mijatovic V, Sapkota Y, Low SK, Zondervan KT, Montgomery GW, Nyholt DR, Van Heel DA, Hunt K, Arking DE, Ashar FN, Sotoodehnia N, Woo D, Rosand J, Comeau ME, Brown WM, Silverman EK, Hokanson JE, Cho MH, Hui J, Ferreira MA, Thompson PJ, Morrison AC, Felix JF, Smith NL, Christiano AM, Petukhova L, Betz RC, Fan X, Zhang X, Zhu C, Langefeld CD, Thompson SD, Wang F, Lin X, Schwartz DA, Fingerlin T, Rotter JI, Cotch MF, Jensen RA, Munz M, Dommisch H, Schaefer AS, Han F, Ollila HM, Hillary RP, Albagha O, Ralston SH, Zeng C, Zheng W, Shu XO, Reis A, Uebe S, Hüffmeier U, Kawamura Y, Otowa T, Sasaki T, Hibberd ML, Davila S, Xie G, Siminovitch K, Bei JX, Zeng YX, Foersti A, Chen B, Landi S, Franke A, Fischer A, Ellinghaus D, Flores C, Noth I, Ma SF, Foo JN, Liu J, Kim JW, Cox DG, Delattre O, Mirabeau O, Skibola CF, Tang CS, Garcia-Barcelo M, Chang KP, Su WH, Chang YS, Martin NG, Gordon S, Wade TD, Lee C, Kubo M, Cha PC, Nakamura Y, Levy D, Kimura M, Hwang SJ, Hunt S, Spector T, Soranzo N, Manichaikul A, Barr G, Kahali B, Speliotes E, Yerges-Armstrong L, Cheng CY, Jonas JB, Wong TY, Fogh I, Lin K, Powell JF, Rice K, Relton CL, Martin RM, Smith GD (2017)


Publication Type: Journal article

Publication year: 2017

Journal

Book Volume: 3

Pages Range: 636-651

Journal Issue: 5

DOI: 10.1001/jamaoncol.2016.5945

Abstract

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.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.Genomewide association studies (GWAS) published up to January 15, 2015.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.Summary association statistics for single nucleotide polymorphisms (SNPs) that are strongly associated with telomere length in the general population.Odds ratios (ORs) and 95% confidence intervals (CIs) for disease per standard deviation (SD) higher telomere length due to germline genetic variation.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]).It is likely that longer telomeres increase risk for several cancers but reduce risk for some non-neoplastic diseases, including cardiovascular diseases.

Authors with CRIS profile

Involved external institutions

Universitätsklinikum Schleswig-Holstein (UKSH) DE Germany (DE) Rutgers, The State University of New Jersey US United States (USA) (US) Framingham Heart Study US United States (USA) (US) Weill Cornell Medicine-Qatar (WCM-Q) QA Qatar (QA) King’s College London GB United Kingdom (GB) Wellcome Trust Sanger Institute - Genome Research Limited GB United Kingdom (GB) University of Virginia (UVA) US United States (USA) (US) Columbia University US United States (USA) (US) University of Michigan US United States (USA) (US) Singapore National Eye Centre (SNEC) SG Singapore (SG) Capital University of Medical Sciences / 首都医科大学 CN China (CN) University of Washington US United States (USA) (US) University of Bristol GB United Kingdom (GB) University of Cambridge GB United Kingdom (GB) The Institute of Cancer Research (ICR) GB United Kingdom (GB) University of Texas MD Anderson Cancer Center US United States (USA) (US) QIMR Berghofer Medical Research Institute (früher: the Queensland Institute of Medical Research) AU Australia (AU) University of Leeds GB United Kingdom (GB) Harvard University US United States (USA) (US) Mount Sinai Hospital (MSH) CA Canada (CA) Dartmouth College US United States (USA) (US) Dana–Farber Cancer Institute US United States (USA) (US) National Cancer Institute (NCI) US United States (USA) (US) National and Kapodistrian University of Athens GR Greece (GR) Universitätsklinikum Heidelberg DE Germany (DE) Catalan Institute of Oncology / Institut Català d'Oncologia (ICO) ES Spain (ES) Deutsches Krebsforschungszentrum (DKFZ) DE Germany (DE) University of Paris 11 - Paris-Sud / Université Paris XI Paris-Sud FR France (FR) Aarhus University DK Denmark (DK) Universitetet i Tromsø / The Arctic University of Norway (UiT) NO Norway (NO) Azienda Ospedaliera Civile M. P.Arezzo IT Italy (IT) Umeå University SE Sweden (SE) University of Otago NZ New Zealand (NZ) University Medical Centre Utrecht (UMC Utrecht) NL Netherlands (NL) University of Leicester GB United Kingdom (GB) University of Stellenbosch / Universiteit van Stellenbosch ZA South Africa (ZA) Geisinger Health System US United States (USA) (US) International Agency for Research on Cancer (IARC) FR France (FR) University of California San Francisco (UCSF) US United States (USA) (US) Memorial Sloan Kettering Cancer Center US United States (USA) (US) Mayo Clinic US United States (USA) (US) Johns Hopkins University (JHU) US United States (USA) (US) Indiana University US United States (USA) (US) University of Pennsylvania US United States (USA) (US) Radboud University Nijmegen NL Netherlands (NL) Helmholtz Zentrum München - Deutsches Forschungszentrum für Gesundheit und Umwelt (HMGU) / Helmholtz Munich DE Germany (DE) National Institute on Alcohol Abuse and Alcoholism (NIAAA) DE Germany (DE) Albert-Ludwigs-Universität Freiburg DE Germany (DE) University of Verona / Università degli Studi di Verona IT Italy (IT) Riken Institute of Physical and Chemical Research / 理研 JP Japan (JP) University of Oxford GB United Kingdom (GB) Queen Mary University of London GB United Kingdom (GB) University of Cincinnati US United States (USA) (US) Massachusetts General Hospital US United States (USA) (US) Wake Forest University US United States (USA) (US) Brigham and Women's Hospital (BWH) US United States (USA) (US) University of Colorado System US United States (USA) (US) Sir Charles Gairdner Hospital AU Australia (AU) University of Western Australia (UWA) AU Australia (AU) University of Texas Health Science Center at Houston (UTHealth) US United States (USA) (US) Erasmus University Medical Center (MC) NL Netherlands (NL) Rheinische Friedrich-Wilhelms-Universität Bonn DE Germany (DE) Anhui Medical University CN China (CN) University of Chinese Academy of Sciences CN China (CN) National Jewish Health US United States (USA) (US) Harbor–UCLA Medical Center US United States (USA) (US) National Eye Institute US United States (USA) (US) Charité - Universitätsmedizin Berlin DE Germany (DE) Peking University (PKU) / 北京大学 CN China (CN) Stanford University US United States (USA) (US) Hamad Bin Khalifa University QA Qatar (QA) University of Edinburgh GB United Kingdom (GB) Vanderbilt University US United States (USA) (US) Shonan Kamakura General Hospital JP Japan (JP) University of Tokyo JP Japan (JP) Genome Institute of Singapore SG Singapore (SG) Sun Yat-Sen University CN China (CN) University of Pisa / Università di Pisa (UniPi) IT Italy (IT) Christian-Albrechts-Universität zu Kiel DE Germany (DE) Universidad de La Laguna ES Spain (ES) University of Chicago US United States (USA) (US) Agency for Science, Technology and Research (A*STAR) SG Singapore (SG) Sungkyunkwan University (SKKU) KR Korea, Republic of (KR) National Institute for Health and Medical Research / Institut national de la santé et de la recherche médicale (INSERM) FR France (FR) PSL Research University / Université de recherche Paris Sciences et Lettres FR France (FR) University of Alabama at Birmingham (UAB) US United States (USA) (US) University of Hong Kong (HKU) / 香港大學 HK Hong Kong (HK) Taoyuan Chang Gung Memorial Hospital TW Taiwan (TW) Chang Gung University (CGU) / 長庚大學 TW Taiwan (TW) Flinders University AU Australia (AU) Soongsil University KR Korea, Republic of (KR) Kobe University / 神戸大学 JP Japan (JP) Imperial College London / The Imperial College of Science, Technology and Medicine GB United Kingdom (GB) Yale University US United States (USA) (US)

How to cite

APA:

Haycock, P.C., Burgess, S., Nounu, A., Zheng, J., Okoli, G.N., Bowden, J.,... Smith, G.D. (2017). Association Between Telomere Length and Risk of Cancer and Non-Neoplastic Diseases: A Mendelian Randomization Study. JAMA Oncology, 3(5), 636-651. https://doi.org/10.1001/jamaoncol.2016.5945

MLA:

Haycock, Philip C., et al. "Association Between Telomere Length and Risk of Cancer and Non-Neoplastic Diseases: A Mendelian Randomization Study." JAMA Oncology 3.5 (2017): 636-651.

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