Konstantinos K Tsilidis1,2, Nikos Papadimitriou3, Niki Dimou3, Dipender Gill2, Sarah J Lewis4,5, Richard M Martin4,5,6, Neil Murphy3, Georgios Markozannes1, Verena Zuber2,7, Amanda J Cross2, Kimberley Burrows4,5, David S Lopez8, Timothy J Key9, Ruth C Travis9, Aurora Perez-Cornago9, David J Hunter9, Fränzel J B van Duijnhoven10, Demetrius Albanes11, Volker Arndt12, Sonja I Berndt11, Stéphane Bézieau13, D Timothy Bishop14, Juergen Boehm15,16, Hermann Brenner12,17,18, Andrea Burnett-Hartman19, Peter T Campbell20, Graham Casey21, Sergi Castellví-Bel22, Andrew T Chan23,24,25,26,27,28, Jenny Chang-Claude29,30, Albert de la Chapelle31,32, Jane C Figueiredo33,34, Steven J Gallinger35, Graham G Giles36,37,38, Phyllis J Goodman39, Andrea Gsur40, Jochen Hampe41, Heather Hampel42, Michael Hoffmeister12, Mark A Jenkins37, Temitope O Keku43, Sun-Seog Kweon44,45, Susanna C Larsson46, Loic Le Marchand47, Christopher I Li48, Li Li49, Annika Lindblom50,51, Vicente Martín52,53, Roger L Milne36,37,38, Victor Moreno52,54,55,56, Hongmei Nan57,58, Rami Nassir59, Polly A Newcomb48,60, Kenneth Offit61,62, Paul D P Pharoah63, Elizabeth A Platz64, John D Potter48,65, Lihong Qi66, Gad Rennert67,68,69, Lori C Sakoda48,70, Clemens Schafmayer71, Martha L Slattery72, Linda Snetselaar73, Jeanette Schenk39, Stephen N Thibodeau74, Cornelia M Ulrich15,16, Bethany Van Guelpen75, Sophia Harlid75, Kala Visvanathan64, Ludmila Vodickova76,77,78, Hansong Wang47, Emily White48,79, Alicja Wolk46, Michael O Woods80, Anna H Wu34, Wei Zheng81, Bas Bueno-de-Mesquita82, Marie-Christine Boutron-Ruault83,84, David J Hughes85, Paula Jakszyn86,87, Tilman Kühn29, Domenico Palli88, Elio Riboli2, Edward L Giovannucci24,27,89, Barbara L Banbury48, Stephen B Gruber34,90, Ulrike Peters48,79, Marc J Gunter3. 1. Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece. 2. Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom. 3. Section of Nutrition and Metabolism, International Agency for Research on Cancer, Lyon, France. 4. Department of Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom. 5. Medical Research Council Integrative Epidemiology Unit, Department of Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom. 6. University Hospitals Bristol National Health Service Foundation Trust National Institute for Health Research Bristol Biomedical Research Centre, University of Bristol, Bristol, United Kingdom. 7. Medical Research Council Biostatistics Unit, School of Clinical Medicine, University of Cambridge, Cambridge, United Kingdom. 8. Department of Preventive Medicine and Community Health, The University of Texas Medical Branch, Galveston, TX, USA. 9. Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom. 10. Division of Human Nutrition and Health, Wageningen University & Research, Wageningen, Netherlands. 11. Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, MD, USA. 12. Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany. 13. Medical Genetics Service, University Hospital Center (CHU) Nantes, Nantes, France. 14. , Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, United Kingdom. 15. Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA. 16. Department of Population Health Sciences, University of Utah, Salt Lake City, UT, USA. 17. Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany. 18. German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany. 19. Institute for Health Research, Kaiser Permanente Colorado, Denver, CO, USA. 20. Behavioral and Epidemiology Research Group, American Cancer Society, Atlanta, GA, USA. 21. Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA. 22. Gastroenterology Department, Hospital Clinic, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Biomedical Research Network Center for Liver and Digestive Diseases (CIBEREHD), University of Barcelona, Barcelona, Spain. 23. Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. 24. Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. 25. Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. 26. Broad Institute of Harvard and MIT, Cambridge, MA, USA. 27. Department of Epidemiology, Harvard TH Chan School of Public Health, Harvard University, Boston, MA, USA. 28. Department of Immunology and Infectious Diseases, Harvard TH Chan School of Public Health, Harvard University, Boston, MA, USA. 29. Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany. 30. University Medical Centre Hamburg-Eppendorf, University Cancer Centre Hamburg, Hamburg, Germany. 31. Department of Cancer Biology and Genetics, The Ohio State University, Columbus, OH, USA. 32. Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA. 33. Department of Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA. 34. Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA. 35. Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada. 36. Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia. 37. Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia. 38. Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, Victoria, Australia. 39. SWOG Statistical Center, Fred Hutchinson Cancer Research Center, Seattle, WA, USA. 40. Institute of Cancer Research, Department of Medicine I, Medical University Vienna, Vienna, Austria. 41. Department of Medicine I, University Hospital Dresden, Dresden University of Technology (TU Dresden), Dresden, Germany. 42. Division of Human Genetics, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA. 43. Center for Gastrointestinal Biology and Disease, University of North Carolina, Chapel Hill, NC, USA. 44. Department of Preventive Medicine, Chonnam National University Medical School, Gwangju, Republic of Korea. 45. Jeonnam Regional Cancer Center, Chonnam National University Hwasun Hospital, Hwasun, Republic of Korea. 46. Institute of Environmental Medicine, Karolinska Institute, Stockholm, Sweden. 47. University of Hawaii Cancer Center, Honolulu, HI, USA. 48. Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA. 49. Department of Family Medicine, University of Virginia, Charlottesville, VA, USA. 50. Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden. 51. Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden. 52. CIBER of Epidemiology and Public Health (CIBERESP), Madrid, Spain. 53. Biomedicine Institute (IBIOMED), University of León, León, Spain. 54. Oncology Data Analytics Program, Catalan Institute of Oncology-Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain. 55. Department of Clinical Sciences, Faculty of Medicine, University of Barcelona, Barcelona, Spain. 56. ONCOBEL Program, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain. 57. Department of Epidemiology, Richard M Fairbanks School of Public Health, Indiana University, Indianapolis, IN, USA. 58. IU Melvin and Bren Simon Cancer Center, Indiana University, Indianapolis, IN, USA. 59. Department of Pathology, School of Medicine, Umm Al-Qura'a University, Mecca, Saudi Arabia. 60. School of Public Health, University of Washington, Seattle, WA, USA. 61. Clinical Genetics Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, USA. 62. Department of Medicine, Weill Cornell Medical College, New York, NY, USA. 63. Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom. 64. Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA. 65. Centre for Public Health Research, Massey University, Wellington, New Zealand. 66. Department of Public Health Sciences, School of Medicine, University of California Davis, Davis, CA, USA. 67. Department of Community Medicine and Epidemiology, Lady Davis Carmel Medical Center, Haifa, Israel. 68. Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel. 69. Clalit National Cancer Control Center, Haifa, Israel. 70. Division of Research, Kaiser Permanente Northern California, Oakland, CA, USA. 71. Department of General Surgery, University Hospital Rostock, Rostock, Germany. 72. Department of Internal Medicine, University of Utah, Salt Lake City, UT, USA. 73. Department of Epidemiology, University of Iowa College of Public Health, Iowa City, IA, USA. 74. Division of Laboratory Genetics, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA. 75. Department of Radiation Sciences, Oncology Unit, Umeå University, Umeå, Sweden. 76. Department of Molecular Biology of Cancer, Institute of Experimental Medicine of the Czech Academy of Sciences, Prague, Czech Republic. 77. Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University, Prague, Czech Republic. 78. Faculty of Medicine and Biomedical Center in Pilsen, Charles University, Pilsen, Czech Republic. 79. Department of Epidemiology, University of Washington, Seattle, WA, USA. 80. Discipline of Genetics, Memorial University of Newfoundland, St. John's, Newfoundland, Canada. 81. Division of Epidemiology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt Epidemiology Center, Vanderbilt University School of Medicine, Nashville, TN, USA. 82. Formerly, Department for Determinants of Chronic Diseases (DCD), National Institute for Public Health and the Environment (RIVM), Bilthoven, Netherlands. 83. Faculty of Medicine, CESP, University of Paris-Sud, Faculty of Medicine UVSQ, INSERM, University of Paris-Saclay, Villejuif, France. 84. Centre for Research in Epidemiology and Population Health (CESP), Gustave Roussy, Villejuif, France. 85. Cancer Biology and Therapeutics Group, UCD Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland. 86. Unit of Nutrition and Cancer, Cancer Epidemiology Research Program, Catalan Institute of Oncology- Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain. 87. Blanquerna Faculty of Health Sciences, Ramon Llull University, Barcelona, Spain. 88. Cancer Risk Factors and Life-Style Epidemiology Unit, Institute for Cancer Research, Prevention and Clinical Network-ISPRO, Florence, Italy. 89. Department of Nutrition, Harvard TH Chan School of Public Health, Harvard University, Boston, MA, USA. 90. USC Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA.
Abstract
BACKGROUND: The literature on associations of circulating concentrations of minerals and vitamins with risk of colorectal cancer is limited and inconsistent. Evidence from randomized controlled trials (RCTs) to support the efficacy of dietary modification or nutrient supplementation for colorectal cancer prevention is also limited. OBJECTIVES: To complement observational and RCT findings, we investigated associations of genetically predicted concentrations of 11 micronutrients (β-carotene, calcium, copper, folate, iron, magnesium, phosphorus, selenium, vitamin B-6, vitamin B-12, and zinc) with colorectal cancer risk using Mendelian randomization (MR). METHODS: Two-sample MR was conducted using 58,221 individuals with colorectal cancer and 67,694 controls from the Genetics and Epidemiology of Colorectal Cancer Consortium, Colorectal Cancer Transdisciplinary Study, and Colon Cancer Family Registry. Inverse variance-weighted MR analyses were performed with sensitivity analyses to assess the impact of potential violations of MR assumptions. RESULTS: Nominally significant associations were noted for genetically predicted iron concentration and higher risk of colon cancer [ORs per SD (ORSD): 1.08; 95% CI: 1.00, 1.17; P value = 0.05] and similarly for proximal colon cancer, and for vitamin B-12 concentration and higher risk of colorectal cancer (ORSD: 1.12; 95% CI: 1.03, 1.21; P value = 0.01) and similarly for colon cancer. A nominally significant association was also noted for genetically predicted selenium concentration and lower risk of colon cancer (ORSD: 0.98; 95% CI: 0.96, 1.00; P value = 0.05) and similarly for distal colon cancer. These associations were robust to sensitivity analyses. Nominally significant inverse associations were observed for zinc and risk of colorectal and distal colon cancers, but sensitivity analyses could not be performed. None of these findings survived correction for multiple testing. Genetically predicted concentrations of β-carotene, calcium, copper, folate, magnesium, phosphorus, and vitamin B-6 were not associated with disease risk. CONCLUSIONS: These results suggest possible causal associations of circulating iron and vitamin B-12 (positively) and selenium (inversely) with risk of colon cancer.
BACKGROUND: The literature on associations of circulating concentrations of minerals and vitamins with risk of colorectal cancer is limited and inconsistent. Evidence from randomized controlled trials (RCTs) to support the efficacy of dietary modification or nutrient supplementation for colorectal cancer prevention is also limited. OBJECTIVES: To complement observational and RCT findings, we investigated associations of genetically predicted concentrations of 11 micronutrients (β-carotene, calcium, copper, folate, iron, magnesium, phosphorus, selenium, vitamin B-6, vitamin B-12, and zinc) with colorectal cancer risk using Mendelian randomization (MR). METHODS: Two-sample MR was conducted using 58,221 individuals with colorectal cancer and 67,694 controls from the Genetics and Epidemiology of Colorectal Cancer Consortium, Colorectal Cancer Transdisciplinary Study, and Colon Cancer Family Registry. Inverse variance-weighted MR analyses were performed with sensitivity analyses to assess the impact of potential violations of MR assumptions. RESULTS: Nominally significant associations were noted for genetically predicted iron concentration and higher risk of colon cancer [ORs per SD (ORSD): 1.08; 95% CI: 1.00, 1.17; P value = 0.05] and similarly for proximal colon cancer, and for vitamin B-12 concentration and higher risk of colorectal cancer (ORSD: 1.12; 95% CI: 1.03, 1.21; P value = 0.01) and similarly for colon cancer. A nominally significant association was also noted for genetically predicted selenium concentration and lower risk of colon cancer (ORSD: 0.98; 95% CI: 0.96, 1.00; P value = 0.05) and similarly for distal colon cancer. These associations were robust to sensitivity analyses. Nominally significant inverse associations were observed for zinc and risk of colorectal and distal colon cancers, but sensitivity analyses could not be performed. None of these findings survived correction for multiple testing. Genetically predicted concentrations of β-carotene, calcium, copper, folate, magnesium, phosphorus, and vitamin B-6 were not associated with disease risk. CONCLUSIONS: These results suggest possible causal associations of circulating iron and vitamin B-12 (positively) and selenium (inversely) with risk of colon cancer.
Authors: David J Hughes; Veronika Fedirko; Mazda Jenab; Lutz Schomburg; Catherine Méplan; Heinz Freisling; H B as Bueno-de-Mesquita; Sandra Hybsier; Niels-Peter Becker; Magdalena Czuban; Anne Tjønneland; Malene Outzen; Marie-Christine Boutron-Ruault; Antoine Racine; Nadia Bastide; Tilman Kühn; Rudolf Kaaks; Dimitrios Trichopoulos; Antonia Trichopoulou; Pagona Lagiou; Salvatore Panico; Petra H Peeters; Elisabete Weiderpass; Guri Skeie; Engeset Dagrun; Maria-Dolores Chirlaque; Maria-Jose Sánchez; Eva Ardanaz; Ingrid Ljuslinder; Maria Wennberg; Kathryn E Bradbury; Paolo Vineis; Alessio Naccarati; Domenico Palli; Heiner Boeing; Kim Overvad; Miren Dorronsoro; Paula Jakszyn; Amanda J Cross; Jose Ramón Quirós; Magdalena Stepien; So Yeon Kong; Talita Duarte-Salles; Elio Riboli; John E Hesketh Journal: Int J Cancer Date: 2014-07-21 Impact factor: 7.396
Authors: Joan Lappe; Patrice Watson; Dianne Travers-Gustafson; Robert Recker; Cedric Garland; Edward Gorham; Keith Baggerly; Sharon L McDonnell Journal: JAMA Date: 2017-03-28 Impact factor: 56.272
Authors: Luigi Ferrucci; John R B Perry; Amy Matteini; Markus Perola; Toshiko Tanaka; Kaisa Silander; Neil Rice; David Melzer; Anna Murray; Christie Cluett; Linda P Fried; Demetrius Albanes; Anna-Maria Corsi; Antonio Cherubini; Jack Guralnik; Stefania Bandinelli; Andrew Singleton; Jarmo Virtamo; Jeremy Walston; Richard D Semba; Timothy M Frayling Journal: Am J Hum Genet Date: 2009-01-29 Impact factor: 11.025
Authors: Bryan Kestenbaum; Nicole L Glazer; Anna Köttgen; Janine F Felix; Shih-Jen Hwang; Yongmei Liu; Kurt Lohman; Stephen B Kritchevsky; Dorothy B Hausman; Ann-Kristin Petersen; Christian Gieger; Janina S Ried; Thomas Meitinger; Tim M Strom; H Erich Wichmann; Harry Campbell; Caroline Hayward; Igor Rudan; Ian H de Boer; Bruce M Psaty; Kenneth M Rice; Yii-Der Ida Chen; Man Li; Dan E Arking; Eric Boerwinkle; Josef Coresh; Qiong Yang; Daniel Levy; Frank J A van Rooij; Abbas Dehghan; Fernando Rivadeneira; André G Uitterlinden; Albert Hofman; Cornelia M van Duijn; Michael G Shlipak; W H Linda Kao; Jacqueline C M Witteman; David S Siscovick; Caroline S Fox Journal: J Am Soc Nephrol Date: 2010-06-17 Impact factor: 10.121
Authors: Vasiliki I Dimitrakopoulou; Konstantinos K Tsilidis; Philip C Haycock; Niki L Dimou; Kawthar Al-Dabhani; Richard M Martin; Sarah J Lewis; Marc J Gunter; Alison Mondul; Irene M Shui; Evropi Theodoratou; Katharina Nimptsch; Sara Lindström; Demetrius Albanes; Tilman Kühn; Timothy J Key; Ruth C Travis; Karani Santhanakrishnan Vimaleswaran; Peter Kraft; Brandon L Pierce; Joellen M Schildkraut Journal: BMJ Date: 2017-10-31
Authors: Conall M O'Seaghdha; Hongsheng Wu; Qiong Yang; Karen Kapur; Idris Guessous; Annie Mercier Zuber; Anna Köttgen; Candice Stoudmann; Alexander Teumer; Zoltán Kutalik; Massimo Mangino; Abbas Dehghan; Weihua Zhang; Gudny Eiriksdottir; Guo Li; Toshiko Tanaka; Laura Portas; Lorna M Lopez; Caroline Hayward; Kurt Lohman; Koichi Matsuda; Sandosh Padmanabhan; Dmitri Firsov; Rossella Sorice; Sheila Ulivi; A Catharina Brockhaus; Marcus E Kleber; Anubha Mahajan; Florian D Ernst; Vilmundur Gudnason; Lenore J Launer; Aurelien Mace; Eric Boerwinckle; Dan E Arking; Chizu Tanikawa; Yusuke Nakamura; Morris J Brown; Jean-Michel Gaspoz; Jean-Marc Theler; David S Siscovick; Bruce M Psaty; Sven Bergmann; Peter Vollenweider; Veronique Vitart; Alan F Wright; Tatijana Zemunik; Mladen Boban; Ivana Kolcic; Pau Navarro; Edward M Brown; Karol Estrada; Jingzhong Ding; Tamara B Harris; Stefania Bandinelli; Dena Hernandez; Andrew B Singleton; Giorgia Girotto; Daniela Ruggiero; Adamo Pio d'Adamo; Antonietta Robino; Thomas Meitinger; Christa Meisinger; Gail Davies; John M Starr; John C Chambers; Bernhard O Boehm; Bernhard R Winkelmann; Jie Huang; Federico Murgia; Sarah H Wild; Harry Campbell; Andrew P Morris; Oscar H Franco; Albert Hofman; Andre G Uitterlinden; Fernando Rivadeneira; Uwe Völker; Anke Hannemann; Reiner Biffar; Wolfgang Hoffmann; So-Youn Shin; Pierre Lescuyer; Hughes Henry; Claudia Schurmann; Patricia B Munroe; Paolo Gasparini; Nicola Pirastu; Marina Ciullo; Christian Gieger; Winfried März; Lars Lind; Tim D Spector; Albert V Smith; Igor Rudan; James F Wilson; Ozren Polasek; Ian J Deary; Mario Pirastu; Luigi Ferrucci; Yongmei Liu; Bryan Kestenbaum; Jaspal S Kooner; Jacqueline C M Witteman; Matthias Nauck; W H Linda Kao; Henri Wallaschofski; Olivier Bonny; Caroline S Fox; Murielle Bochud Journal: PLoS Genet Date: 2013-09-19 Impact factor: 5.917