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Association between pre-diagnostic circulating vitamin D concentration and risk of colorectal cancer in European populations:a nested case-control study

BMJ 2010; 340 doi: (Published 22 January 2010) Cite this as: BMJ 2010;340:b5500
  1. Mazda Jenab, scientist1,
  2. H Bas Bueno-de-Mesquita, senior scientist233,
  3. Pietro Ferrari, scientist13,
  4. Franzel J B van Duijnhoven, scientist24,
  5. Teresa Norat, principal research fellow5,
  6. Tobias Pischon, scientist6,
  7. Eugène H J M Jansen, scientist2,
  8. Nadia Slimani, scientist, group head1,
  9. Graham Byrnes, statistician1,
  10. Sabina Rinaldi, scientist1,
  11. Anne Tjønneland, department head7,
  12. Anja Olsen, scientist7,
  13. Kim Overvad, professor of epidemiology8,
  14. Marie-Christine Boutron-Ruault, senior scientist9,
  15. Françoise Clavel-Chapelon, department head9,
  16. Sophie Morois, research fellow9,
  17. Rudolf Kaaks, professor, division head10,
  18. Jakob Linseisen, unit head1034,
  19. Heiner Boeing, professor, department chair6,
  20. Manuela M Bergmann, scientist6,
  21. Antonia Trichopoulou, professor of nutrition1112,
  22. Gesthimani Misirli, research associate11,
  23. Dimitrios Trichopoulos, professor of cancer prevention, professor of epidemiology13,
  24. Franco Berrino, department chief14,
  25. Paolo Vineis, chair of environmental epidemiology, unit chief515,
  26. Salvatore Panico, professor of internal medicine, unit chief 16,
  27. Domenico Palli, unit chief17,
  28. Rosario Tumino, director18,
  29. Martine M Ros, junior scientist219,
  30. Carla H van Gils, associate professor of clinical epidemiology4,
  31. Petra H Peeters, professor of epidemiology4,
  32. Magritt Brustad, researcher20,
  33. Eiliv Lund, professor20,
  34. María-José Tormo, unit chief, scientist2122,
  35. Eva Ardanaz, scientist23,
  36. Laudina Rodríguez, section chief24,
  37. Maria-José Sánchez, lecturer, director2526,
  38. Miren Dorronsoro, unit chief27,
  39. Carlos A Gonzalez, scientist, unit chief28,
  40. Göran Hallmans, professor29,
  41. Richard Palmqvist, senior lecturer, consultant30,
  42. Andrew Roddam, visiting research fellow31,
  43. Timothy J Key, deputy director31,
  44. Kay-Tee Khaw, professor of clinical gerontology32,
  45. Philippe Autier, scientist, section head1,
  46. Pierre Hainaut, scientist, section head1,
  47. Elio Riboli, director5
  1. 1International Agency for Research on Cancer (IARC-WHO), Lyon, France
  2. 2National Institute for Public Health and the Environment (RIVM), Bilthoven, Netherlands
  3. 3Data Collection and Exposure Unit, European Food Safety Authority (EFSA), Parma, Italy
  4. 4Julius Centre for Health Sciences and Primary Care, University Medical Centre, Utrecht, Netherlands
  5. 5School of Public Health, Imperial College, London, UK
  6. 6Department of Epidemiology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany
  7. 7Institute of Cancer Epidemiology, Danish Cancer Society, Copenhagen, Denmark
  8. 8Department of Epidemiology, School of Public Health, Aarhus University, Aarhus, Denmark
  9. 9Inserm (Institut National de la Santé et de la Recherche Médicale) ERI 20, EA 4045, and Institut Gustave Roussy, Villejuif, France
  10. 10Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany
  11. 11Department of Hygiene and Epidemiology, University of Athens Medical School, Greece
  12. 12Hellenic Health Foundation, Greece
  13. 13Department of Epidemiology, Harvard School of Public Health, USA and Bureau of Epidemiologic Research, Academy of Athens, Greece
  14. 14Department of Preventive and Predictive Medicine, Etiologic Epidemiology and Prevention Unit, Fondazione IRCCS Istituto Nazionale dei Tumori (National Cancer Institute), Milan, Italy
  15. 15ISI Foundation, Turin, Italy
  16. 16Department of Clinical and Experimental Medicine, Federico II University, Naples, Italy
  17. 17Molecular and Nutritional Epidemiology Unit, ISPO (Cancer Research and Prevention Institute), Florence, Italy
  18. 18Ragusa Cancer Registry and Histopathology Unit, “Civile M.P.Arezzo” Hospital, ASP 7 Ragusa, Italy
  19. 19Department of Epidemiology, Biostatistics and HTA, Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands
  20. 20Centre for Sami Health Research, Institute of Community Medicine, University of Tromsø, Tromsø, Norway
  21. 21Epidemiology Service, Murcia Regional Health Authority, Spain
  22. 22CIBER Epidemiología y Salud Pública (CIBERESP), Spain
  23. 23Public Health Institute of Navarra, Pamplona, Spain. CIBER Epidemiología y Salud Pública (CIBERESP), Spain
  24. 24Health Information Section, Public Health and Participation Directorate, Health and Health Care Services Council, Asturias, Spain
  25. 25Andalusian School of Public Health-Granada (Spain)
  26. 26CIBER Epidemiología y Salud Pública (CIBERESP), Spain
  27. 27Epidemiology Unit, Public Health Division of Guipuzkoa, San Sebastian, Spain
  28. 28Unit of Nutrition, Environment and Cancer, Cancer Epidemiology Research Programme, Catalan Institute of Oncology (ICO-IDIBELL), Barcelona, Spain
  29. 29Department of Public Health and Clinical Medicine, Nutritional Research, Umeå, Sweden
  30. 30Department of Medical Biosciences, Pathology, Umeå University, Umeå, Sweden
  31. 31Cancer Epidemiology Unit, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK
  32. 32Clinical Gerontology Unit, University of Cambridge, Cambridge, UK
  33. 33Department of Gastroenterology and Hepatology, University Medical Centre, Utrecht, Netherlands
  34. 34Institute of Epidemiology, Helmholtz Zentrum München, Neuherberg, Germany
  1. Correspondence to: M Jenab, Lifestyle and Cancer Group, International Agency for Research on Cancer, Lyon, France Jenab{at}


    Objective To examine the association between pre-diagnostic circulating vitamin D concentration, dietary intake of vitamin D and calcium, and the risk of colorectal cancer in European populations.

    Design Nested case-control study.

    Setting The study was conducted within the EPIC study, a cohort of more than 520 000 participants from 10 western European countries.

    Participants 1248 cases of incident colorectal cancer, which developed after enrolment into the cohort, were matched to 1248 controls

    Main outcome measures Circulating vitamin D concentration (25-hydroxy-vitamin-D, 25-(OH)D) was measured by enzyme immunoassay. Dietary and lifestyle data were obtained from questionnaires. Incidence rate ratios and 95% confidence intervals for the risk of colorectal cancer by 25-(OH)D concentration and levels of dietary calcium and vitamin D intake were estimated from multivariate conditional logistic regression models, with adjustment for potential dietary and other confounders.

    Results 25-(OH)D concentration showed a strong inverse linear dose-response association with risk of colorectal cancer (P for trend <0.001). Compared with a pre-defined mid-level concentration of 25-(OH)D (50.0-75.0 nmol/l), lower levels were associated with higher colorectal cancer risk (<25.0 nmol/l: incidence rate ratio 1.32 (95% confidence interval 0.87 to 2.01); 25.0-49.9 nmol/l: 1.28 (1.05 to 1.56), and higher concentrations associated with lower risk (75.0-99.9 nmol/l: 0.88 (0.68 to 1.13); ≥100.0 nmol/l: 0.77 (0.56 to 1.06)). In analyses by quintile of 25-(OH)D concentration, patients in the highest quintile had a 40% lower risk of colorectal cancer than did those in the lowest quintile (P<0.001). Subgroup analyses showed a strong association for colon but not rectal cancer (P for heterogeneity=0.048). Greater dietary intake of calcium was associated with a lower colorectal cancer risk. Dietary vitamin D was not associated with disease risk. Findings did not vary by sex and were not altered by corrections for season or month of blood donation.

    Conclusions The results of this large observational study indicate a strong inverse association between levels of pre-diagnostic 25-(OH)D concentration and risk of colorectal cancer in western European populations. Further randomised trials are needed to assess whether increases in circulating 25-(OH)D concentration can effectively decrease the risk of colorectal cancer.


    • We are very grateful to Sheila Bingham who contributed greatly to the present manuscript, but sadly died between the time from submission to final acceptance and did not have an opportunity to approve the final version. We also thank Paolo Boffetta for his many comments and input into the manuscript, C Biessy and B Hemon for their assistance in database preparation and statistical analyses, and J Cremers and P Beekhof for their laboratory assistance in the vitamin D analyses.

    • Contributors: ER is the overall coordinator of the EPIC study, which he conceptualised, designed, and implemented in collaboration with the main investigators in the collaborating centres: Denmark: ATjønneland, KO; France: MCBR, FCC; Germany: RK, JL, HB; Greece: ATrichopoulou, DT; Italy: FB, PV, SP, DP, RT; Netherlands: HBBdM, PHP; Norway: EL; Spain: MJT, EA, LRS; MJS, MD, CAG; Sweden: GH; UK: TJK, KTK, Sheila Bingham; IARC: Paolo Boffetta. All authors contributed to recruitment, data collection/acquisition and/or biological sample collection, and are responsible for the ongoing follow-up and management of the EPIC cohort. All coauthors commented on and approved the study proposal. This article was written by MJ with assistance from HBBdM, FJBvD, TN, NS, SR, TP, EHJMJ, PA, and ER, and taking into account the comments and suggestions of the coauthors. All coauthors had the opportunity to comment on the analysis and interpretation of the findings and approved the final version for publication. The grant application for this study was written by MJ and ER. Statistical expertise and input was provided by PF, GB, and AR. The laboratory analyses were done by EHJMJ.

    • Funding: We thank the World Cancer Research Fund (WCRF, London, UK; grant number 2005/12) for grant funding for the present study. The EPIC study was supported by the Europe Against Cancer Programme of the European Commission (SANCO); Ligue contre le Cancer (France); Mutuelle Générale de l’Education Nationale; Institut National de la Santé et de la Recherche Médicale (INSERM); German Cancer Aid; German Cancer Research Center; German Federal Ministry of Education and Research; Danish Cancer Society; Health Research Fund (FIS) of the Spanish Ministry of Health (RETIC-RD06/0020); the participating regional governments and institutions of Spain; The ISCIII Red de Centro RCESP (C03/09); Cancer Research UK; Medical Research Council, UK; the Stroke Association, UK; British Heart Foundation; Department of Health, UK; Food Standards Agency, UK; the Wellcome Trust, UK; Greek Ministry of Health and Social Solidarity; Hellenic Health Foundation and Stavros Niarchos Foundation; Greek Ministry of Education; Italian Association for Research on Cancer; Italian National Research Council; Compagnia di San Paolo; Dutch Ministry of Public Health, Welfare and Sports; Dutch Ministry of Health; Dutch Prevention Funds; LK Research Funds; Dutch ZON (Zorg Onderzoek Nederland); Swedish Cancer Society; Swedish Scientific Council; Regional Governments of Skane and Vasterbotten, Sweden; and Norwegian Cancer Society.

    • Competing interests: None declared.

    • Ethical approval: This study was approved by the ethics review boards of the International Agency for Research on Cancer and individual EPIC centres. EPIC participants provided written consent for the use of their blood samples and all data.

    • Data sharing: No additional data available.

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