Philip C Haycock1, Stephen Burgess2, Aayah Nounu1, Jie Zheng1, George N Okoli3, Jack Bowden1, Kaitlin Hazel Wade1, Nicholas J Timpson1, David M Evans4, Peter Willeit5, Abraham Aviv6, Tom R Gaunt1, Gibran Hemani1, Massimo Mangino7, Hayley Patricia Ellis8, Kathreena M Kurian8, Karen A Pooley9, Rosalind A Eeles10, Jeffrey E Lee11, Shenying Fang11, Wei V Chen12, Matthew H Law13, Lisa M Bowdler14, Mark M Iles15, Qiong Yang16, Bradford B Worrall17, Hugh Stephen Markus18, Rayjean J Hung19, Chris I Amos20, Amanda B Spurdle21, Deborah J Thompson9, Tracy A O'Mara21, Brian Wolpin22, Laufey Amundadottir23, Rachael Stolzenberg-Solomon24, Antonia Trichopoulou25, N Charlotte Onland-Moret26, Eiliv Lund27, Eric J Duell28, Federico Canzian29, Gianluca Severi30, Kim Overvad31, Marc J Gunter32, Rosario Tumino33, Ulrika Svenson34, Andre van Rij35, Annette F Baas36, Matthew J Bown37, Nilesh J Samani37, Femke N G van t'Hof38, Gerard Tromp39, Gregory T Jones35, Helena Kuivaniemi39, James R Elmore40, Mattias Johansson41, James Mckay42, Ghislaine Scelo41, Robert Carreras-Torres41, Valerie Gaborieau41, Paul Brennan41, Paige M Bracci43, Rachel E Neale14, Sara H Olson44, Steven Gallinger45, Donghui Li46, Gloria M Petersen47, Harvey A Risch48, Alison P Klein49, Jiali Han50, Christian C Abnet51, Neal D Freedman51, Philip R Taylor51, John M Maris52, Katja K Aben53, Lambertus A Kiemeney54, Sita H Vermeulen54, John K Wiencke55, Kyle M Walsh55, Margaret Wrensch55, Terri Rice56, Clare Turnbull57, Kevin Litchfield58, Lavinia Paternoster1, Marie Standl59, Gonçalo R Abecasis60, John Paul SanGiovanni61, Yong Li62, Vladan Mijatovic63, Yadav Sapkota14, Siew-Kee Low64, Krina T Zondervan65, Grant W Montgomery14, Dale R Nyholt66, David A van Heel67, Karen Hunt67, Dan E Arking68, Foram N Ashar68, Nona Sotoodehnia69, Daniel Woo70, Jonathan Rosand71, Mary E Comeau72, W Mark Brown72, Edwin K Silverman73, John E Hokanson74, Michael H Cho73, Jennie Hui75, Manuel A Ferreira14, Philip J Thompson76, Alanna C Morrison77, Janine F Felix78, Nicholas L Smith79, Angela M Christiano80, Lynn Petukhova81, Regina C Betz82, Xing Fan83, Xuejun Zhang83, Caihong Zhu83, Carl D Langefeld72, Susan D Thompson84, Feijie Wang85, Xu Lin85, David A Schwartz86, Tasha Fingerlin87, Jerome I Rotter88, Mary Frances Cotch89, Richard A Jensen90, Matthias Munz91, Henrik Dommisch92, Arne S Schaefer92, Fang Han93, Hanna M Ollila94, Ryan P Hillary94, Omar Albagha95, Stuart H Ralston96, Chenjie Zeng97, Wei Zheng97, Xiao-Ou Shu97, Andre Reis98, Steffen Uebe98, Ulrike Hüffmeier98, Yoshiya Kawamura99, Takeshi Otowa100, Tsukasa Sasaki101, Martin Lloyd Hibberd102, Sonia Davila103, Gang Xie104, Katherine Siminovitch104, Jin-Xin Bei105, Yi-Xin Zeng106, Asta Försti107, Bowang Chen108, Stefano Landi109, Andre Franke110, Annegret Fischer111, David Ellinghaus112, Carlos Flores113, Imre Noth114, Shwu-Fan Ma114, Jia Nee Foo115, Jianjun Liu115, Jong-Won Kim116, David G Cox117, Olivier Delattre118, Olivier Mirabeau118, Christine F Skibola119, Clara S Tang120, Merce Garcia-Barcelo120, Kai-Ping Chang121, Wen-Hui Su122, Yu-Sun Chang123, Nicholas G Martin14, Scott Gordon14, Tracey D Wade124, Chaeyoung Lee125, Michiaki Kubo126, Pei-Chieng Cha127, Yusuke Nakamura128, Daniel Levy129, Masayuki Kimura6, Shih-Jen Hwang129, Steven Hunt130, Tim Spector131, Nicole Soranzo132, Ani W Manichaikul133, R Graham Barr134, Bratati Kahali135, Elizabeth Speliotes135, Laura M Yerges-Armstrong136, Ching-Yu Cheng137, Jost B Jonas138, Tien Yin Wong137, Isabella Fogh139, Kuang Lin139, John F Powell139, Kenneth Rice140, Caroline L Relton1, Richard M Martin141, George Davey Smith1. 1. MRC Integrative Epidemiology Unit, University of Bristol, Bristol, England2School of Social and Community Medicine, University of Bristol, Bristol, England. 2. Department of Public Health and Primary Care, University of Cambridge, Cambridge, England. 3. School of Social and Community Medicine, University of Bristol, Bristol, England. 4. MRC Integrative Epidemiology Unit, University of Bristol, Bristol, England2School of Social and Community Medicine, University of Bristol, Bristol, England4University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Queensland, Australia. 5. Department of Public Health and Primary Care, University of Cambridge, Cambridge, England5Department of Neurology, Innsbruck Medical University, Austria. 6. Center of Human Development and Aging, Department of Pediatrics, New Jersey Medical School, Rutgers, The State University of New Jersey. 7. Department of Twin Research and Genetic Epidemiology, King's College London, London England8NIHR Biomedical Research Centre at Guy's and St Thomas' Foundation Trust, London, England. 8. Brain Tumour Research Group, Institute of Clinical Neuroscience, Learning and Research Building, Southmead Hospital, University of Bristol. 9. Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, England. 10. The Institute of Cancer Research and Royal Marsden NHS Foundation Trust, London, England. 11. Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston. 12. Department of Clinical Applications & Support, The University of Texas MD Anderson Cancer Center, Houston. 13. Statistical Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Australia. 14. QIMR Berghofer Medical Research Institute, Brisbane, Australia. 15. Section of Epidemiology and Biostatistics, Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, England. 16. Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts. 17. Departments of Neurology and Public Health Sciences, University of Virginia Charlottesville, Virginia. 18. Department of Clinical Neurosciences, University of Cambridge, England. 19. Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Ontario, Canada21Division of Epidemiology, Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada. 20. Geisel School of Medicine, Dartmouth College, Hanover, New Hampshire. 21. Genetics and Computational Biology Division, QIMR Berghofer Medical Research Institute, Brisbane, Australia. 22. Dana-Farber Cancer Institute, Boston, Massachusetts. 23. Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland. 24. Metabolic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland. 25. Hellenic Health Foundation, Athens, Greece28WHO Collaborating Center for Nutrition and Health, Unit of Nutritional Epidemiology and Nutrition in Public Health, Department of Hygiene, Epidemiology and Medical Statistics, University of Athens Medical School, Athens, Greece. 26. Department of Epidemiology, Julius Center for Health Sciences and Primary Care, University Medical Center, Utrecht, the Netherlands. 27. Institute of Community Medicine, UiT The Arctic University of Norway, Tromso, Norway. 28. Unit of Nutrition and Cancer, Cancer Epidemiology Research Program, Bellvitge Biomedical Research Institute (IDIBELL), Catalan Institute of Oncology (ICO), L'Hospitalet de Llobregat, Barcelona, Spain. 29. Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany. 30. Université Paris-Saclay, Université Paris-Sud, UVSQ, CESP, INSERM, Villejuif, France34Institut Gustave Roussy, Villejuif, France35Human Genetics Foundation (HuGeF), Torino, Italy36Cancer Council Victoria and University of Melbourne, Melbourne, Australia. 31. Department of Public Health, Section for Epidemiology, Aarhus University, Aarhus, Denmark. 32. School of Public Health, Imperial College London, London, England. 33. Cancer Registry, Azienda Ospedaliera "Civile M.P. Arezzo," Ragusa, Italy. 34. Department of Medical Biosciences, Umea University, Umea, Sweden. 35. Surgery Department, University of Otago, Dunedin, New Zealand. 36. Department of Genetics, University Medical Center Utrecht, Utrecht, the Netherlands. 37. Department of Cardiovascular Sciences and the NIHR Leicester, Cardiovascular Biomedical Research Unit, University of Leicester, Glenfield Hospital, Leicester, England. 38. Department of Neurology and Neurosurgery, Brain Center Rudolf Magnus, University Medical Center Utrecht, The Netherlands. 39. Division of Molecular Biology and Human Genetics, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg, South Africa46The Sigfried and Janet Weis Center for Research, Geisinger Health System, Danville, Pennsylvania. 40. Department of Vascular and Endovascular Surgery, Geisinger Health System, Danville, Pennsylvania. 41. Genetic Epidemiology Group, International Agency for Research on Cancer, Lyon, France. 42. Genetic Cancer Susceptibility Group, International Agency for Research on Cancer, Lyon, France. 43. Department of Epidemiology and Biostatistics, University of California San Francisco. 44. Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York. 45. Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Ontario, Canada. 46. Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston. 47. Department of Health Sciences Research, Mayo Clinic College of Medicine, Rochester, Minnesota. 48. Yale School of Public Health, Yale School of Medicine, and Yale Cancer Center, New Haven, Connecticut. 49. Departments of Oncology, Pathology and Epidemiology, Johns Hopkins School of Medicine, Baltimore, Maryland. 50. Department of Epidemiology, Fairbanks School of Public Health, Indiana University, Indianapolis57Indiana University Melvin and Bren Simon Cancer Center, Indianapolis. 51. Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland. 52. Children's Hospital of Philadelphia, Perelman School of Medicine at the University of Pennsylvania. 53. Radboud University Medical Center, Radboud Institute for Health Sciences, Nijmegen, The Netherlands61Netherlands Comprehensive Cancer Organization, Utrecht, The Netherlands. 54. Radboud University Medical Center, Radboud Institute for Health Sciences, Nijmegen, The Netherlands. 55. Department of Neurological Surgery, University of California, San Francisco, San Francisco, California63Institute of Human Genetics, University of California, San Francisco, San Francisco, California. 56. Department of Neurological Surgery, University of California, San Francisco, San Francisco, California. 57. The Institute of Cancer Research and Royal Marsden NHS Foundation Trust, London, England64William Harvey Research Institute, Queen Mary University, London, England. 58. Division of Genetics and Epidemiology, The Institute of Cancer Research, London, England. 59. Institute of Epidemiology I, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany. 60. Department of Biostatistics, University of Michigan, Ann Arbor. 61. National Institute of Alcohol Abuse and Alcoholism, Laboratory of Membrane Biophysics and Biochemistry, Section on Nutritional Neuroscience, Bethesda, Maryland69Department of Biochemistry and Molecular and Cellular Biology, Georgetown School of Medicine, Washington, DC. 62. Division of Genetic Epidemiology, Institute for Medical Biometry and Statistics, Faculty of Medicine, and Medical Centre, University of Freiburg, Freiburg, Germany. 63. Department of Life and Reproduction Sciences, University of Verona, Verona, Italy. 64. Laboratory of Statistical Analysis, Centre for Integrative Medical Sciences, The Institute of Physical and Chemical Research (RIKEN), Yokohama, Japan. 65. Genetic and Genomic Epidemiology Unit, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, England74Nuffield Department of Obstetrics and Gynecology, University of Oxford, John Radcliffe Hospital, Oxford, England. 66. QIMR Berghofer Medical Research Institute, Brisbane, Australia75Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Australia. 67. Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, England. 68. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland. 69. Division of Cardiology and Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, Washington. 70. University of Cincinnati College of Medicine, Department of Neurology, Cincinnati, Ohio. 71. Massachusetts General Hospital, Neurology, Center for Human Genetic Research, Boston, Massachusetts. 72. Center for Public Health Genomics, Department of Biostatistical Sciences, Division of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, North Carolina. 73. Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, Massachusetts. 74. Department of Epidemiology, University of Colorado Anschutz Medical Campus, Aurora, Colorado. 75. Busselton Population Medical Research Institute Inc, Sir Charles Gairdner Hospital, Perth, Australia85PathWest Laboratory Medicine of Western Australia, Perth, Australia86School of Pathology and Laboratory Medicine, University of Western Australia, Perth, Australia87School of Population Health, University of WA, Perth, Australia. 76. The Lung Health Clinic and Institute for Respiratory Health, University of Western Australia, Perth, Australia. 77. Department of Epidemiology, Human Genetics, and Environmental Sciences, University of Texas Health Science Center at Houston, Houston. 78. Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands. 79. Department of Epidemiology, University of Washington, Seattle. 80. Departments of Dermatology and Genetics & Development, Columbia University, New York, New York. 81. Departments of Dermatology and Epidemiology, Columbia University, New York, New York. 82. Institute of Human Genetics, University of Bonn, Bonn, Germany. 83. Institute of Dermatology & Department of Dermatology, First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China. 84. Center for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio. 85. Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China. 86. Department of Medicine, School of Medicine, University of Colorado, Aurora. 87. Department of Biomedical Research, National Jewish Health Hospital, Denver, Colorado. 88. Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California101Departments of Pediatrics and Medicine, Harbor-UCLA Medical Center, Torrance, California. 89. Epidemiology Branch, Division of Epidemiology and Clinical Applications, Intramural Research Program, National Eye Institute, National Institutes of Health, Clinical Research Center, Bethesda, Maryland. 90. Cardiovascular Health Research Unit, University of Washington, Seattle104Department of Medicine, University of Washington, Seattle. 91. Department of Periodontology and Synoptic Dentistry, Center for Dental and Craniofacial Sciences, Charité - University Medicine Berlin, Berlin, Germany106Institute for Integrative and Experimental Genomics, University of Lübeck, Lübeck, Germany. 92. Department of Periodontology and Synoptic Dentistry, Center for Dental and Craniofacial Sciences, Charité - University Medicine Berlin, Berlin, Germany. 93. Department of Pulmonary Medicine, Peking University People's Hospital, Beijing, China. 94. Stanford University, Center for Sleep Sciences, Palo Alto, California. 95. Qatar Biomedical Research Institute, Hamad Bin Khalifa University, Doha, Qatar110Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, Scotland. 96. Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, Scotland. 97. Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee. 98. Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany. 99. Department of Psychiatry, Shonan Kamakura General Hospital, Kanagawa, Japan. 100. Department of Neuropsychiatry, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan115Graduate School of Clinical Psychology, Teikyo Heisei University Major of Professional Clinical Psychology, Tokyo, Japan. 101. Department of Physical and Health Education, Graduate School of Education, University of Tokyo, Tokyo, Japan. 102. Infectious Diseases, Genome Institute of Singapore, Singapore. 103. Human Genetics, Genome Institute of Singapore, Singapore. 104. Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Ontario, Canada119Departments of Medicine, Immunology, Molecular Genetics, University of Toronto, Toronto, Ontario, Canada. 105. Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China. 106. Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China121Peking Union Medical College, Beijing, China. 107. Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany123Center for Primary Health Care Research, Clinical Research Center, Lund University, Malmö, Sweden. 108. Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany. 109. Department of Biology, University of Pisa, Pisa, Italy. 110. University Hospital Schleswig-Holstein, Kiel, Germany. 111. University Hospital Schleswig-Holstein, Kiel, Germany126Institute of Clinical Molecular Biology, Kiel University, Kiel, Germany. 112. Institute of Clinical Molecular Biology, Kiel University, Kiel, Germany. 113. Research Unit, Hospital Universitario N.S. de Candelaria, Universidad de La Laguna, Tenerife, Spain128CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain. 114. Section of Pulmonary and Critical Care Medicine, University of Chicago, Chicago, Illinois. 115. Human Genetics, Genome Institute of Singapore, A*STAR, Singapore. 116. Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan, University School of Medicine, Gangnam-gu, Seoul, South Korea. 117. Cancer Research Center of Lyon, INSERM U1052, Lyon, France. 118. Inserm U830, Institut Curie, PSL University, Paris, France. 119. Department of Epidemiology, University of Alabama at Birmingham. 120. Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong. 121. Department of Otolaryngology-Head and Neck Surgery, Chang Gung Memorial Hospital at Lin-Kou, Taoyuan, Taiwan. 122. Department of Otolaryngology-Head and Neck Surgery, Chang Gung Memorial Hospital at Lin-Kou, Taoyuan, Taiwan137Department of Biomedical Sciences, Graduate Institute of Biomedical Sciences, College of Medicine, Molecular Medicine Research Center, Chang Gung University, Taoyuan, Taiwan. 123. Molecular Medicine Research Center, Chang Gung University, Taoyuan, Taiwan. 124. School of Psychology, Flinders University, Adelaide, South Australia. 125. School of Systems Biomedical Science, Soongsil University, Dongjak-gu, Seoul, South Korea. 126. RIKEN Center for Integrative Medical Science, Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa, Japan. 127. Division of Molecular Brain Science, Kobe University Graduate School of Medicine, Kusunoki-chou, Chuo-ku, Kobe, Japan. 128. Center for Personalized Therapeutics, The University of Chicago, Chicago, Illinois. 129. The NHLBI's Framingham Heart Study, Framingham, Massachusetts, Population Sciences Branch of the National Heart, Lung, and Blood Institute, Bethesda, Maryland. 130. Department of Genetic Medicine, Weill Cornell Medicine in Qatar, Doha, Qatar. 131. Department of Twin Research and Genetic Epidemiology, King's College London, London England. 132. Human Genetics, Wellcome Trust Sanger Institute, Genome Campus, Hinxton Cambridge, England. 133. Center for Public Health Genomics, Department of Public Health Sciences, University of Virginia, Charlottesville. 134. Department of Medicine and Department of Epidemiology, Columbia University Medical Center, New York, New York. 135. Department of Internal Medicine, Division of Gastroenterology and Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor. 136. Department of Medicine, University of Maryland, Baltimore. 137. Singapore Eye Research Institute, Singapore National Eye Center, Singapore152Department of Ophthalmology, National University of Singapore and National University Health System, Singapore153Duke-NUS Medical School, Singapore. 138. Beijing Institute of Ophthalmology, Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University, Beijing Ophthalmology and Visual Science Key Laboratory, Beijing, China155Department of Ophthalmology, Medical Faculty Mannheim of the Ruprecht-Karls-University Heidelberg, Mannheim, Germany. 139. Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, England. 140. Department of Biostatistics, University of Washington, Seattle. 141. MRC Integrative Epidemiology Unit, University of Bristol, Bristol, England2School of Social and Community Medicine, University of Bristol, Bristol, England158University of Bristol/University Hospitals Bristol NHS Foundation Trust National Institute for Health Research Bristol Nutrition Biomedical Research Unit, Bristol, England.
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.
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.
Authors: James R Elmore; Melissa A Obmann; Helena Kuivaniemi; Gerard Tromp; Glenn S Gerhard; David P Franklin; Amy M Boddy; David J Carey Journal: J Vasc Surg Date: 2009-06 Impact factor: 4.268
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Authors: Mark P Purdue; Mattias Johansson; Diana Zelenika; Jorge R Toro; Ghislaine Scelo; Lee E Moore; Egor Prokhortchouk; Xifeng Wu; Lambertus A Kiemeney; Valerie Gaborieau; Kevin B Jacobs; Wong-Ho Chow; David Zaridze; Vsevolod Matveev; Jan Lubinski; Joanna Trubicka; Neonila Szeszenia-Dabrowska; Jolanta Lissowska; Péter Rudnai; Eleonora Fabianova; Alexandru Bucur; Vladimir Bencko; Lenka Foretova; Vladimir Janout; Paolo Boffetta; Joanne S Colt; Faith G Davis; Kendra L Schwartz; Rosamonde E Banks; Peter J Selby; Patricia Harnden; Christine D Berg; Ann W Hsing; Robert L Grubb; Heiner Boeing; Paolo Vineis; Françoise Clavel-Chapelon; Domenico Palli; Rosario Tumino; Vittorio Krogh; Salvatore Panico; Eric J Duell; José Ramón Quirós; Maria-José Sanchez; Carmen Navarro; Eva Ardanaz; Miren Dorronsoro; Kay-Tee Khaw; Naomi E Allen; H Bas Bueno-de-Mesquita; Petra H M Peeters; Dimitrios Trichopoulos; Jakob Linseisen; Börje Ljungberg; Kim Overvad; Anne Tjønneland; Isabelle Romieu; Elio Riboli; Anush Mukeria; Oxana Shangina; Victoria L Stevens; Michael J Thun; W Ryan Diver; Susan M Gapstur; Paul D Pharoah; Douglas F Easton; Demetrius Albanes; Stephanie J Weinstein; Jarmo Virtamo; Lars Vatten; Kristian Hveem; Inger Njølstad; Grethe S Tell; Camilla Stoltenberg; Rajiv Kumar; Kvetoslava Koppova; Olivier Cussenot; Simone Benhamou; Egbert Oosterwijk; Sita H Vermeulen; Katja K H Aben; Saskia L van der Marel; Yuanqing Ye; Christopher G Wood; Xia Pu; Alexander M Mazur; Eugenia S Boulygina; Nikolai N Chekanov; Mario Foglio; Doris Lechner; Ivo Gut; Simon Heath; Hélène Blanche; Amy Hutchinson; Gilles Thomas; Zhaoming Wang; Meredith Yeager; Joseph F Fraumeni; Konstantin G Skryabin; James D McKay; Nathaniel Rothman; Stephen J Chanock; Mark Lathrop; Paul Brennan Journal: Nat Genet Date: 2010-12-05 Impact factor: 38.330
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