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Circulating vitamin D concentration and risk of seven cancers: Mendelian randomisation study

BMJ 2017; 359 doi: https://doi.org/10.1136/bmj.j4761 (Published 31 October 2017) Cite this as: BMJ 2017;359:j4761
  1. Vasiliki I Dimitrakopoulou, lecturer1 2,
  2. Konstantinos K Tsilidis, assistant professor1 3,
  3. Philip C Haycock, senior research associate4 5,
  4. Niki L Dimou, postdoctoral fellow1,
  5. Kawthar Al-Dabhani, research fellow3,
  6. Richard M Martin, professor46,
  7. Sarah J Lewis, senior lecturer4 5,
  8. Marc J Gunter, section and group head7,
  9. Alison Mondul, assistant professor8,
  10. Irene M Shui, research associate9,
  11. Evropi Theodoratou, reader10,
  12. Katharina Nimptsch, research associate11,
  13. Sara Lindström, assistant professor12,
  14. Demetrius Albanes, senior investigator13,
  15. Tilman Kühn, research associate14,
  16. Timothy J Key, professor15,
  17. Ruth C Travis, associate professor15,
  18. Karani Santhanakrishnan Vimaleswaran, lecturer16,
  19. the GECCO Consortium,
  20. the PRACTICAL Consortium,
  21. the GAME-ON Network (CORECT, DRIVE, ELLIPSE, FOCI-OCAC, TRICL-ILCCO),
  22. Peter Kraft, professor17,
  23. Brandon L Pierce, assistant professor1820,
  24. Joellen M Schildkraut, professor21
  1. 1Department of Hygiene and Epidemiology, School of Medicine, University of Ioannina, Ioannina, Greece
  2. 2School of Mathematics and Statistics, University College Dublin, Dublin, Ireland
  3. 3Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK
  4. 4School of Social and Community Medicine, University of Bristol, Bristol, UK
  5. 5MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK
  6. 6National Institute for Health Research (NIHR) Bristol Nutritional Biomedical Research Unit, University Hospitals Bristol NHS Foundation Trust and the University of Bristol, Bristol, UK
  7. 7International Agency for Research on Cancer, Lyon, France
  8. 8Department of Epidemiology, University of Michigan School of Public Health, Ann Arbor, MI, USA
  9. 9Department of Epidemiology, Harvard School of Public Health, Boston, MA, USA
  10. 10Centre of Global Health Research, Usher Institute for Population Health Sciences and Informatics, University of Edinburg, Edinburgh, UK
  11. 11Molecular Epidemiology Research Group, Max Delbrück Centre for Molecular Medicine (MDC), Berlin, Germany
  12. 12Department of Epidemiology, University of Washington, Seattle, WA, USA
  13. 13Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA
  14. 14Division of Cancer Epidemiology, German Cancer Research Centre (DKFZ), Heidelberg, Germany
  15. 15Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK
  16. 16Department of Food and Nutritional Sciences, Hugh Sinclair Unit of Human Nutrition and Institute for Cardiovascular and Metabolic Research (ICMR), University of Reading, Reading, UK
  17. 17Program in Genetic Epidemiology and Statistical Genetics, Department of Epidemiology, Harvard School of Public Health, Boston, MA, USA
  18. 18Department of Public Health Sciences, University of Chicago, Chicago, IL, USA
  19. 19Comprehensive Cancer Center, University of Chicago, Chicago, IL, USA
  20. 20Department of Human Genetics, University of Chicago, Chicago, IL, USA
  21. 21Department of Public Health Sciences, University of Virginia, Charlottesville, VA, USA
  1. Correspondence to: K K Tsilidis ktsilidi{at}cc.uoi.gr
  • Accepted 26 September 2017

Abstract

Objective To determine if circulating concentrations of vitamin D are causally associated with risk of cancer.

Design Mendelian randomisation study.

Setting Large genetic epidemiology networks (the Genetic Associations and Mechanisms in Oncology (GAME-ON), the Genetic and Epidemiology of Colorectal Cancer Consortium (GECCO), and the Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL) consortiums, and the MR-Base platform).

Participants 70 563 cases of cancer (22 898 prostate cancer, 15 748 breast cancer, 12 537 lung cancer, 11 488 colorectal cancer, 4369 ovarian cancer, 1896 pancreatic cancer, and 1627 neuroblastoma) and 84 418 controls.

Exposures Four single nucleotide polymorphisms (rs2282679, rs10741657, rs12785878 and rs6013897) associated with vitamin D were used to define a multi-polymorphism score for circulating 25-hydroxyvitamin D (25(OH)D) concentrations.

Main outcomes measures The primary outcomes were the risk of incident colorectal, breast, prostate, ovarian, lung, and pancreatic cancer and neuroblastoma, which was evaluated with an inverse variance weighted average of the associations with specific polymorphisms and a likelihood based approach. Secondary outcomes based on cancer subtypes by sex, anatomic location, stage, and histology were also examined.

Results There was little evidence that the multi-polymorphism score of 25(OH)D was associated with risk of any of the seven cancers or their subtypes. Specifically, the odds ratios per 25 nmol/L increase in genetically determined 25(OH)D concentrations were 0.92 (95% confidence interval 0.76 to 1.10) for colorectal cancer, 1.05 (0.89 to 1.24) for breast cancer, 0.89 (0.77 to 1.02) for prostate cancer, and 1.03 (0.87 to 1.23) for lung cancer. The results were consistent with the two different analytical approaches, and the study was powered to detect relative effect sizes of moderate magnitude (for example, 1.20-1.50 per 25 nmol/L decrease in 25(OH)D for most primary cancer outcomes. The Mendelian randomisation assumptions did not seem to be violated.

Conclusions There is little evidence for a linear causal association between circulating vitamin D concentration and risk of various types of cancer, though the existence of causal clinically relevant effects of low magnitude cannot be ruled out. These results, in combination with previous literature, provide evidence that population-wide screening for vitamin D deficiency and subsequent widespread vitamin D supplementation should not currently be recommended as a strategy for primary cancer prevention.

Footnotes

  • Members of the collaboration: Vasiliki I Dimitrakopoulou (Department of Hygiene and Epidemiology, School of Medicine, University of Ioannina, Ioannina, Greece; School of Mathematics and Statistics, University College Dublin, Dublin, Ireland); Konstantinos K Tsilidis (Department of Hygiene and Epidemiology, School of Medicine, University of Ioannina, Ioannina, Greece; Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK); Philip C Haycock and Sarah J Lewis (School of Social and Community Medicine and MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK); Niki L Dimou (Department of Hygiene and Epidemiology, School of Medicine, University of Ioannina, Ioannina, Greece); Kawthar Al-Dabhani (Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK); Richard M Martin (School of Social and Community Medicine and MRC Integrative Epidemiology Unit, University of Bristol, Bristol; National Institute for Health Research (NIHR) Bristol Nutritional Biomedical Research Unit, University Hospitals Bristol NHS Foundation Trust and the University of Bristol, Bristol, UK); Marc J Gunter and Paul Brennan (International Agency for Research on Cancer, Lyon, France); Alison Mondul (Department of Epidemiology, University of Michigan School of Public Health, Ann Arbor, MI, US); Irene M Shui (Department of Epidemiology, Harvard School of Public Health, Boston, MA, US); Evropi Theodoratou (Centre of Global Health Research, Usher Institute for Population Health Sciences and Informatics, University of Edinburg, UK); Katharina Nimptsch (Molecular Epidemiology Research Group, Max Delbrück Center for Molecular Medicine (MDC), Berlin, Germany); Sara Lindström (Department of Epidemiology, University of Washington, Seattle, WA, US); Demetrius Albanes and Sonja I Berndt (Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, US); Tilman Kühn (Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany); Timothy J Key and Ruth C Travis (Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK); Leonid Raskin (Epidemiology Center, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, TN, US); Andrew T Chan (Massachusetts General Hospital, Clinical and Translational Epidemiology Unit and Massachusetts General Hospital, Boston; Division of Gastroenterology, Boston; Brigham and Women’s Hospital, Channing Division of Network Medicine, Boston, MA, US); Mingyang Song (Massachusetts General Hospital, Clinical and Translational Epidemiology Unit and Division of Gastroenterology, Boston, MA; Harvard T.H. Chan School of Public Health, Departments of Nutrition and Epidemiology, Boston, MA, US); Amit D Joshi (Program in Genetic Epidemiology and Statistical Genetics, Department of Epidemiology, Harvard School of Public Health, Boston, MA, US); Yong-Bing Xiang (SKLORG & Department of Epidemiology, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China); Sun Ha Jee (Graduate School of Public Health, Yonsei University, Seoul, Korea); Cornelia M Ulrich (Huntsman Cancer Institute and Department of Population Health Sciences, University of Utah School of Medicine, Salt Lake City, UT, US); John A Baron (Department of Medicine, School of Medicine, University of North Carolina, Chapel Hill, NC, USA); Graham G Giles (Cancer Epidemiology & Intelligence Division, Cancer Council Victoria, Melbourne, Australia; Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of Melbourne; Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Vic, Australia); Robert J MacInnis (Cancer Epidemiology & Intelligence Division, Cancer Council Victoria, Melbourne; Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of Melbourne, Vic, Australia); Melissa C Southey (Genetic Epidemiology Laboratory, Department of Pathology, University of Melbourne, Melbourne, Australia); Jane C Figueiredo (Department of Preventive Medicine, Keck School Of Medicine, University of Southern California; Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, US); Li Li (Department of Family Medicine and Community Health, Case Western Reserve University, Cleveland, OH, US); Christopher A Haiman (Department of Preventive Medicine, Keck School Of Medicine, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, US); Victoria Stevens (Epidemiology Research Program, American Cancer Society, Atlanta, GA, US); Neil Caporaso (Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, US); Christopher I Amos, Department of Biomedical Data Sciences, Geisel School of Medicine at Dartmouth, Lebanon, NH, US); Xifeng Wu (University of Texas MD Anderson Cancer Center, Houston, TX, US); Rayjean J Hung (Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada); Heike Bickeböller (Department of Genetic Epidemiology, University Medical Centre, Georg-August-Universität Göttingen, Göttingen, Germany); Angela Risch (Division of Cancer Genetics/Epigenetics, Department of Molecular Biology, University of Salzburg, Salzburg, Austria; Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center (DKFZ), Heidelberg, Germany; Translational Lung Research Centre Heidelberg, German Center for Lung Research (DZL), Heidelberg, Germany); H-Erich Wichmann (Institute of Medical Informatics, Biometry and Epidemiology, Ludwig Maximilians University, Munich; Helmholtz Center Munich, Institute of Epidemiology II; Institute of Medical Statistics and Epidemiology, Technical University Munich, Germany); Richard Houlston (Division of Genetics and Epidemiology, Institute of Cancer Research, London, UK); Barbara L Banbury (Fred Hutchinson Cancer Research Center, Seattle, WA, US); Stephane Bezieau (Service de Génétique Médicale, Centre Hospitalier Universitaire (CHU) Nantes, Nantes, France); Hermann Brenner (Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg; Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg; German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany); Peter T Campbell (Epidemiology Research Program, American Cancer Society, Atlanta, GA, US); Graham Casey (Department of Public Health Sciences, University of Virginia, Charlottesville, VA, US); Jenny Chang-Claude (Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg; Genetic Cancer Epidemiology, University Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany); Steven J Gallinger (Department of Surgery, Mount Sinai Hospital, TN, Canada); Michael Hoffmeister (Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany); Mark A Jenkins (Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of Melbourne, Vic, Australia); Loic Le Marchand (Epidemiology Program, University of Hawaii Cancer Center, Honololu, HI, US); Polly A Newcomb, Ulrike Peters, and Emily White (Fred Hutchinson Cancer Research Center, Seattle; Department of Epidemiology, University of Washington School of Public Health, Seattle, WA, USA); Martha L Slattery (Department of Internal Medicine, University of Utah Health Sciences Center, Salt Lake City, UT, US); Karani Santhanakrishnan Vimaleswaran (Department of Food and Nutritional Sciences, Hugh Sinclair Unit of Human Nutrition and Institute for Cardiovascular and Metabolic Research (ICMR), University of Reading, Reading, UK); Habibul Ahsan and Brandon L Pierce (Department of Public Health Sciences and Comprehensive Cancer Center and Department of Human Genetics, University of Chicago, Chicago, IL, US); the PRACTICAL Consortium (see appendix 4 for members from the Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL) consortium. Information of the consortium can be found at http://practical.ccge.medschl.cam.ac.uk/); Peter Kraft (Program in Genetic Epidemiology and Statistical Genetics, Department of Epidemiology, Harvard School of Public Health, Boston, MA, US); Joellen M Schildkraut (Department of Public Health Sciences, University of Virginia, Charlottesville, VA, US).

  • Contributors: VID and KKT contributed equally in this paper. The study was conceived and designed by PK, BLP, JMS and KKT. The data were analysed by VID, KKT, PCH, NLD, and KA-D. The first draft of the manuscript was prepared by VID and KKT, which was edited with the input from the writing team (RMM, SJL, MJG, AM, IMS, ET, KN, SL, DA, TK, TJK, and RCT). All other authors provided the data and revised the manuscript critically for important intellectual content. All authors gave final approval of the version to be published and have contributed to the manuscript. VID and KKT are guarantors.

  • Funding: This work was supported by the Genetic Associations and Mechanisms in Oncology Network, GAME-ON: Discovery, Biology, and Risk of Inherited Variants in Breast Cancer, DRIVE, PI: D.J.H. (U19 CA148065); Colorectal Transdisciplinary Study, CORECT (U19 CA148107); Transdisciplinary Research in Cancer of the Lung of the International Lung Cancer Consortium, TRICL-ILCCO (U19 CA148127); Follow-up of ovarian cancer genetic association and interaction studies, FOCI (U19 CA148112); Elucidating Loci Involved in Prostate Cancer Susceptibility, ELLIPSE (U19 CA148537); Genetics and Epidemiology of Colorectal Cancer Consortium, GECCO: National Cancer Institute, National Institutes of Health, US Department of Health and Human Services (U01 CA137088, R01 CA059045). VID and KKT were supported by the World Cancer Research Fund International Regular Grant Programme (WCRF 2014/1180 to KKT). RMM and SL are supported by a Cancer Research UK (C18281/A19169) programme grant (the integrative cancer epidemiology programme). RMM is supported by the National Institute for Health Research (NIHR), Bristol Nutritional Biomedical Research Unit based at University Hospitals Bristol NHS Foundation Trust, and the University of Bristol. RCT was supported by Cancer Research UK (C8221/A19170). ET is supported by a chancellor’s fellowship from the University of Edinburgh. None of the funders had any influence on the study design; in the collection, analysis, and interpretation of data; in the writing of the report; and in the decision to submit the article for publication. Further information on funding and acknowledgements is provided in appendix 4.

  • Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf and declare: no undeclared support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work.

  • Ethical approval: Not required.

  • Data sharing: No additional data available.

  • Transparency: The lead authors affirm that the manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned have been explained.

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