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.

Behavioral and Epidemiology Research Group American Cancer Society Atlanta GA USA

Biomedicine Institute University of León León Spain

Blanquerna Faculty of Health Sciences Ramon Llull University Barcelona Spain

Broad Institute of Harvard and MIT Cambridge MA USA

Cancer Biology and Therapeutics Group UCD Conway Institute of Biomolecular and Biomedical Research University College Dublin Dublin Ireland

Cancer Epidemiology Division Cancer Council Victoria Melbourne Victoria Australia

Cancer Risk Factors and Life Style Epidemiology Unit Institute for Cancer Research Prevention and Clinical Network ISPRO Florence Italy

Center for Gastrointestinal Biology and Disease University of North Carolina Chapel Hill NC USA

Center for Public Health Genomics University of Virginia Charlottesville VA USA

Centre for Epidemiology and Biostatistics Melbourne School of Population and Global Health The University of Melbourne Melbourne Victoria Australia

Centre for Public Health Research Massey University Wellington New Zealand

Centre for Research in Epidemiology and Population Health Gustave Roussy Villejuif France

Channing Division of Network Medicine Brigham and Women's Hospital and Harvard Medical School Boston MA USA

CIBER of Epidemiology and Public Health Madrid Spain

Clalit National Cancer Control Center Haifa Israel

Clinical and Translational Epidemiology Unit Massachusetts General Hospital and Harvard Medical School Boston MA USA

Clinical Genetics Service Department of Medicine Memorial Sloan Kettering Cancer Center New York NY USA

Comprehensive Cancer Center The Ohio State University Columbus OH USA

Department of Cancer Biology and Genetics The Ohio State University Columbus OH USA

Department of Clinical Genetics Karolinska University Hospital Stockholm Sweden

Department of Clinical Sciences Faculty of Medicine University of Barcelona Barcelona Spain

Department of Community Medicine and Epidemiology Lady Davis Carmel Medical Center Haifa Israel

Department of Epidemiology and Biostatistics School of Public Health Imperial College London London United Kingdom

Department of Epidemiology Harvard TH Chan School of Public Health Harvard University Boston MA USA

Department of Epidemiology Johns Hopkins Bloomberg School of Public Health Baltimore MD USA

Department of Epidemiology Richard M Fairbanks School of Public Health Indiana University Indianapolis IN USA

Department of Epidemiology University of Iowa College of Public Health Iowa City IA USA

Department of Epidemiology University of Washington Seattle WA USA

Department of Family Medicine University of Virginia Charlottesville VA USA

Department of General Surgery University Hospital Rostock Rostock Germany

Department of Hygiene and Epidemiology University of Ioannina School of Medicine Ioannina Greece

Department of Immunology and Infectious Diseases Harvard TH Chan School of Public Health Harvard University Boston MA USA

Department of Internal Medicine University of Utah Salt Lake City UT USA

Department of Medicine 1 University Hospital Dresden Dresden University of Technology Dresden Germany

Department of Medicine Samuel Oschin Comprehensive Cancer Institute Cedars Sinai Medical Center Los Angeles CA USA

Department of Medicine Weill Cornell Medical College New York NY USA

Department of Molecular Biology of Cancer Institute of Experimental Medicine of the Czech Academy of Sciences Prague Czech Republic

Department of Molecular Medicine and Surgery Karolinska Institute Stockholm Sweden

Department of Nutrition Harvard TH Chan School of Public Health Harvard University Boston MA USA

Department of Pathology School of Medicine Umm Al Qura'a University Mecca Saudi Arabia

Department of Population Health Sciences Bristol Medical School University of Bristol Bristol United Kingdom

Department of Population Health Sciences University of Utah Salt Lake City UT USA

Department of Preventive Medicine and Community Health The University of Texas Medical Branch Galveston TX USA

Department of Preventive Medicine Chonnam National University Medical School Gwangju Republic of Korea

Department of Preventive Medicine Keck School of Medicine University of Southern California Los Angeles CA USA

Department of Public Health and Primary Care University of Cambridge Cambridge United Kingdom

Department of Public Health Sciences School of Medicine University of California Davis Davis CA USA

Department of Radiation Sciences Oncology Unit Umeå University Umeå Sweden

Discipline of Genetics Memorial University of Newfoundland St John's Newfoundland Canada

Division of Cancer Epidemiology and Genetics National Cancer Institute NIH Bethesda MD USA

Division of Cancer Epidemiology German Cancer Research Center Heidelberg Germany

Division of Clinical Epidemiology and Aging Research German Cancer Research Center Heidelberg Germany

Division of Epidemiology Department of Medicine Vanderbilt Ingram Cancer Center Vanderbilt Epidemiology Center Vanderbilt University School of Medicine Nashville TN USA

Division of Gastroenterology Massachusetts General Hospital and Harvard Medical School Boston MA USA

Division of Human Genetics Department of Internal Medicine The Ohio State University Columbus OH USA

Division of Human Nutrition and Health Wageningen University and Research Wageningen Netherlands

Division of Laboratory Genetics Department of Laboratory Medicine and Pathology Mayo Clinic Rochester MN USA

Division of Preventive Oncology German Cancer Research Center Heidelberg Germany

Division of Research Kaiser Permanente Northern California Oakland CA USA

Faculty of Medicine and Biomedical Center in Pilsen Charles University Pilsen Czech Republic

Faculty of Medicine CESP University of Paris Sud Faculty of Medicine UVSQ INSERM University of Paris Saclay Villejuif France

Formerly Department for Determinants of Chronic Diseases Bilthoven Netherlands

Gastroenterology Department Hospital Clinic August Pi i Sunyer Biomedical Research Institute University of Barcelona Barcelona Spain

German Cancer Consortium Heidelberg Germany

Huntsman Cancer Institute University of Utah Salt Lake City UT USA

Institute for Health Research Kaiser Permanente Colorado Denver CO USA

Institute of Biology and Medical Genetics 1st Faculty of Medicine Charles University Prague Czech Republic

Institute of Cancer Research Department of Medicine 1 Medical University Vienna Vienna Austria

Institute of Environmental Medicine Karolinska Institute Stockholm Sweden

IU Melvin and Bren Simon Cancer Center Indiana University Indianapolis IN USA

Jeonnam Regional Cancer Center Chonnam National University Hwasun Hospital Hwasun Republic of Korea

Leeds Institute of Cancer and Pathology University of Leeds Leeds United Kingdom

Lunenfeld Tanenbaum Research Institute Mount Sinai Hospital University of Toronto Toronto Ontario Canada

Medical Genetics Service University Hospital Center Nantes Nantes France

Medical Research Council Biostatistics Unit School of Clinical Medicine University of Cambridge Cambridge United Kingdom

Medical Research Council Integrative Epidemiology Unit Department of Population Health Sciences Bristol Medical School University of Bristol Bristol United Kingdom

Nuffield Department of Population Health University of Oxford Oxford United Kingdom

ONCOBEL Program Bellvitge Biomedical Research Institute L'Hospitalet de Llobregat Barcelona Spain

Oncology Data Analytics Program Catalan Institute of Oncology Bellvitge Biomedical Research Institute L'Hospitalet de Llobregat Barcelona Spain

Precision Medicine School of Clinical Sciences at Monash Health Monash University Clayton Victoria Australia

Public Health Sciences Division Fred Hutchinson Cancer Research Center Seattle WA USA

Ruth and Bruce Rappaport Faculty of Medicine Technion Israel Institute of Technology Haifa Israel

School of Public Health University of Washington Seattle WA USA

Section of Nutrition and Metabolism International Agency for Research on Cancer Lyon France

SWOG Statistical Center Fred Hutchinson Cancer Research Center Seattle WA USA

Unit of Nutrition and Cancer Cancer Epidemiology Research Program Catalan Institute of Oncology Bellvitge Biomedical Research Institute L'Hospitalet de Llobregat Barcelona Spain

University Hospitals Bristol National Health Service Foundation Trust National Institute for Health Research Bristol Biomedical Research Centre University of Bristol Bristol United Kingdom

University Medical Centre Hamburg Eppendorf University Cancer Centre Hamburg Hamburg Germany

University of Hawaii Cancer Center Honolulu HI USA

USC Norris Comprehensive Cancer Center University of Southern California Los Angeles CA USA

Erratum v

Am J Clin Nutr. 2021 Jun 1;113(6):1715. doi: 10.1093/ajcn/nqab156. PubMed

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