M Nitter1, B Norgård1, S de Vogel2, S J P M Eussen3, K Meyer4, A Ulvik4, P M Ueland5, O Nygård6, S E Vollset7, T Bjørge7, A Tjønneland8, L Hansen8, M Boutron-Ruault9, A Racine9, V Cottet10, R Kaaks11, T Kühn11, A Trichopoulou12, C Bamia12, A Naska12, S Grioni13, D Palli14, S Panico15, R Tumino16, P Vineis17, H B Bueno-de-Mesquita18, H van Kranen19, P H Peeters20, E Weiderpass21, M Dorronsoro22, P Jakszyn23, M Sánchez24, M Argüelles25, J M Huerta26, A Barricarte27, M Johansson28, I Ljuslinder29, K Khaw30, N Wareham31, H Freisling32, T Duarte-Salles32, M Stepien32, M J Gunter33, E Riboli33. 1. Departments of Global Public Health and Primary Care. 2. Departments of Global Public Health and Primary Care stefan.vogel@isf.uib.no. 3. Departments of Global Public Health and Primary Care Clinical Science, Section for Pharmacology, University of Bergen, Bergen, Norway Department of Epidemiology, School for Public Health and Primary Care, CAPHRI, Maastricht University, Maastricht, The Netherlands. 4. BEVITAL AS, Bergen. 5. Clinical Science, Section for Pharmacology, University of Bergen, Bergen, Norway Laboratory of Clinical Biochemistry, Haukeland University Hospital, Bergen. 6. Departments of Clinical Science, Section of Cardiology, University of Bergen, Bergen Heart Disease, Haukeland University Hospital, Bergen. 7. Departments of Global Public Health and Primary Care Norwegian Institute of Public Health, Bergen, Norway. 8. Institute of Cancer Epidemiology, Danish Cancer Society, Copenhagen, Denmark. 9. INSERM, Centre for Research in Epidemiology and Population Health (CESP), Nutrition, Hormones and Women's Health Team, Villejuif Paris South University, Villejuif IGR, Villejuif. 10. INSERM, Research Centre 'Lipids, Nutrition, Cancer', Dijon, France. 11. German Cancer Research Center (DKFZ), Heidelberg, Germany. 12. Hellenic Health Foundation, Athens WHO Collaborating Center for Food and Nutrition Policies, Department of Hygiene, Epidemiology and Medical Statistics, University of Athens Medical School, Athens, Greece. 13. Epidemiology and Prevention Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano. 14. Molecular and Nutritional Epidemiology Unit, Cancer Research and Prevention Institute-ISPO, Florence. 15. Dipartimento di Medicina Clinica e Chirurgia, Federico II University, Naples. 16. Cancer Registry and Histopathology Unit, 'Civile - M.P. Arezzo' Hospital, ASP, Ragusa. 17. School of Public Health and HuGeF Foundation, Torino, Italy The School of Public Health, Imperial College London, London, UK. 18. The School of Public Health, Imperial College London, London, UK National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands Department of Gastroenterology and Hepatology. 19. National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands. 20. The School of Public Health, Imperial College London, London, UK Julius Center for Health Sciences and Primary Care, University Medical Center, Utrecht, The Netherlands. 21. Department of Community Medicine, Faculty of Health Sciences, UIT The Arctic University of Norway, Tromsø Department of Research, Cancer Registry of Norway, Oslo, Norway Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden Department of Genetic Epidemiology, Samfundet Folkhälsan, Helsinki, Finland. 22. Basque Regional Health Department, Public Health Direction and Biodonostia Research Institute (CIBERESP), San Sebastian. 23. Unit of Nutrition, Environment and Cancer, Cancer Epidemiology Research Program, Catalan Institute of Oncology, Barcelona. 24. Andalusian School of Public Health, Granada CIBER de Epidemiología y Salud Pública (CIBERESP), Madrid Instituto de Investigación Biosanitaria de Granada (Granada.ibs), Granada. 25. Public Health Directorate, Asturias, Oviedo. 26. CIBER de Epidemiología y Salud Pública (CIBERESP), Madrid Department of Epidemiology, Regional Health Council, Murcia. 27. Public Health Institute of Navarra, Pamplona Consortium for Biomedical Research in Epidemiology and Public Health, Madrid, Spain. 28. Department of Biobank Research, Umeå University, Umeå, Sweden International Agency for Research on Cancer (IARC-WHO), Lyon, France. 29. Department of Radiation Sciences, Oncology, University of Umeå, Umeå, Sweden. 30. University of Cambridge School of Clinical Medicine, Cambridge. 31. MRC Epidemiology Unit, University of Cambridge, Cambridge, UK. 32. International Agency for Research on Cancer (IARC-WHO), Lyon, France. 33. The School of Public Health, Imperial College London, London, UK.
Abstract
BACKGROUND: Disturbances in one carbon metabolism may contribute to carcinogenesis by affecting methylation and synthesis of DNA. Choline and its oxidation product betaine are involved in this metabolism and can serve as alternative methyl group donors when folate status is low. PATIENTS AND METHODS: We conducted a case-control study nested within the European Prospective Investigation into Cancer and Nutrition (EPIC), to investigate plasma concentrations of the methyl donors methionine, choline, betaine (trimethylglycine), and dimethylglycine (DMG) in relation to colorectal cancer (CRC) risk. Our study included 1367 incident CRC cases (965 colon and 402 rectum) and 2323 controls matched by gender, age group, and study center. Multivariate-adjusted odds ratios (ORs) and 95% confidence intervals (95% CIs) for CRC risk were estimated by conditional logistic regression, comparing the fifth to the first quintile of plasma concentrations. RESULTS: Overall, methionine (OR: 0.79, 95% CI: 0.63-0.99, P-trend = 0.05), choline (OR: 0.77, 95% CI: 0.60-0.99, P-trend = 0.07), and betaine (OR: 0.85, 95% CI: 0.66-1.09, P-trend = 0.06) concentrations were inversely associated with CRC risk of borderline significance. In participants with folate concentration below the median of 11.3 nmol/l, high betaine concentration was associated with reduced CRC risk (OR: 0.71, 95% CI: 0.50-1.00, P-trend = 0.02), which was not observed for those having a higher folate status. Among women, but not men, high choline concentration was associated with decreased CRC risk (OR: 0.62, 95% CI: 0.43-0.88, P-trend = 0.01). Plasma DMG was not associated with CRC risk. CONCLUSIONS: Individuals with high plasma concentrations of methionine, choline, and betaine may be at reduced risk of CRC.
BACKGROUND: Disturbances in one carbon metabolism may contribute to carcinogenesis by affecting methylation and synthesis of DNA. Choline and its oxidation product betaine are involved in this metabolism and can serve as alternative methyl group donors when folate status is low. PATIENTS AND METHODS: We conducted a case-control study nested within the European Prospective Investigation into Cancer and Nutrition (EPIC), to investigate plasma concentrations of the methyl donors methionine, choline, betaine (trimethylglycine), and dimethylglycine (DMG) in relation to colorectal cancer (CRC) risk. Our study included 1367 incident CRC cases (965 colon and 402 rectum) and 2323 controls matched by gender, age group, and study center. Multivariate-adjusted odds ratios (ORs) and 95% confidence intervals (95% CIs) for CRC risk were estimated by conditional logistic regression, comparing the fifth to the first quintile of plasma concentrations. RESULTS: Overall, methionine (OR: 0.79, 95% CI: 0.63-0.99, P-trend = 0.05), choline (OR: 0.77, 95% CI: 0.60-0.99, P-trend = 0.07), and betaine (OR: 0.85, 95% CI: 0.66-1.09, P-trend = 0.06) concentrations were inversely associated with CRC risk of borderline significance. In participants with folate concentration below the median of 11.3 nmol/l, high betaine concentration was associated with reduced CRC risk (OR: 0.71, 95% CI: 0.50-1.00, P-trend = 0.02), which was not observed for those having a higher folate status. Among women, but not men, high choline concentration was associated with decreased CRC risk (OR: 0.62, 95% CI: 0.43-0.88, P-trend = 0.01). Plasma DMG was not associated with CRC risk. CONCLUSIONS: Individuals with high plasma concentrations of methionine, choline, and betaine may be at reduced risk of CRC.
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