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Genetically predicted circulating concentrations of micronutrients and risk of colorectal cancer among individuals of European descent: a Mendelian randomization study.
Pubmed ID
33740060 (View this publication on the PubMed website)
Digital Object Identifier
Am J Clin Nutr. 2021 Jun 1; Volume 113 (Issue 6): Pages 1490-1502
Tsilidis KK, Papadimitriou N, Dimou N, Gill D, Lewis SJ, Martin RM, Murphy N, Markozannes G, Zuber V, Cross AJ, Burrows K, Lopez DS, Key TJ, Travis RC, Perez-Cornago A, Hunter DJ, van Duijnhoven FJB, Albanes D, Arndt V, Berndt SI, more Bézieau S, Bishop DT, Boehm J, Brenner H, Burnett-Hartman A, Campbell PT, Casey G, Castellví-Bel S, Chan AT, Chang-Claude J, de la Chapelle A, Figueiredo JC, Gallinger SJ, Giles GG, Goodman PJ, Gsur A, Hampe J, Hampel H, Hoffmeister M, Jenkins MA, Keku TO, Kweon SS, Larsson SC, Le Marchand L, Li CI, Li L, Lindblom A, Martín V, Milne RL, Moreno V, Nan H, Nassir R, Newcomb PA, Offit K, Pharoah PDP, Platz EA, Potter JD, Qi L, Rennert G, Sakoda LC, Schafmayer C, Slattery ML, Snetselaar L, Schenk J, Thibodeau SN, Ulrich CM, Van Guelpen B, Harlid S, Visvanathan K, Vodickova L, Wang H, White E, Wolk A, Woods MO, Wu AH, Zheng W, Bueno-de-Mesquita B, Boutron-Ruault MC, Hughes DJ, Jakszyn P, Kühn T, Palli D, Riboli E, Giovannucci EL, Banbury BL, Gruber SB, Peters U, Gunter MJ
  • Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece.
  • Section of Nutrition and Metabolism, International Agency for Research on Cancer, Lyon, France.
  • Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom.
  • Department of Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom.
  • Department of Preventive Medicine and Community Health, The University of Texas Medical Branch, Galveston, TX, USA.
  • Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom.
  • Division of Human Nutrition and Health, Wageningen University & Research, Wageningen, Netherlands.
  • Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, MD, USA.
  • Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • Medical Genetics Service, University Hospital Center (CHU) Nantes, Nantes, France. more
  • , Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, United Kingdom.
  • Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA.
  • Institute for Health Research, Kaiser Permanente Colorado, Denver, CO, USA.
  • Behavioral and Epidemiology Research Group, American Cancer Society, Atlanta, GA, USA.
  • Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA.
  • 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.
  • Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
  • Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • Department of Cancer Biology and Genetics, The Ohio State University, Columbus, OH, USA.
  • Department of Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
  • Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada.
  • Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia.
  • SWOG Statistical Center, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
  • Institute of Cancer Research, Department of Medicine I, Medical University Vienna, Vienna, Austria.
  • Department of Medicine I, University Hospital Dresden, Dresden University of Technology (TU Dresden), Dresden, Germany.
  • Division of Human Genetics, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA.
  • Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia.
  • Center for Gastrointestinal Biology and Disease, University of North Carolina, Chapel Hill, NC, USA.
  • Department of Preventive Medicine, Chonnam National University Medical School, Gwangju, Republic of Korea.
  • Institute of Environmental Medicine, Karolinska Institute, Stockholm, Sweden.
  • University of Hawaii Cancer Center, Honolulu, HI, USA.
  • Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
  • Department of Family Medicine, University of Virginia, Charlottesville, VA, USA.
  • Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden.
  • CIBER of Epidemiology and Public Health (CIBERESP), Madrid, Spain.
  • Department of Epidemiology, Richard M Fairbanks School of Public Health, Indiana University, Indianapolis, IN, USA.
  • Department of Pathology, School of Medicine, Umm Al-Qura'a University, Mecca, Saudi Arabia.
  • Clinical Genetics Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
  • Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom.
  • Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
  • Department of Public Health Sciences, School of Medicine, University of California Davis, Davis, CA, USA.
  • Department of Community Medicine and Epidemiology, Lady Davis Carmel Medical Center, Haifa, Israel.
  • Department of General Surgery, University Hospital Rostock, Rostock, Germany.
  • Department of Internal Medicine, University of Utah, Salt Lake City, UT, USA.
  • Department of Epidemiology, University of Iowa College of Public Health, Iowa City, IA, USA.
  • Division of Laboratory Genetics, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
  • Department of Radiation Sciences, Oncology Unit, Umeå University, Umeå, Sweden.
  • Department of Molecular Biology of Cancer, Institute of Experimental Medicine of the Czech Academy of Sciences, Prague, Czech Republic.
  • Discipline of Genetics, Memorial University of Newfoundland, St. John's, Newfoundland, Canada.
  • Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
  • Division of Epidemiology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt Epidemiology Center, Vanderbilt University School of Medicine, Nashville, TN, USA.
  • Formerly, Department for Determinants of Chronic Diseases (DCD), National Institute for Public Health and the Environment (RIVM), Bilthoven, Netherlands.
  • Faculty of Medicine, CESP, University of Paris-Sud, Faculty of Medicine UVSQ, INSERM, University of Paris-Saclay, Villejuif, France.
  • Cancer Biology and Therapeutics Group, UCD Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland.
  • Unit of Nutrition and Cancer, Cancer Epidemiology Research Program, Catalan Institute of Oncology- Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain.
  • Cancer Risk Factors and Life-Style Epidemiology Unit, Institute for Cancer Research, Prevention and Clinical Network-ISPRO, Florence, Italy.
  • Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.

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.

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