Genetically predicted circulating concentrations of micronutrients and risk of colorectal cancer among individuals of European descent: A Mendelian randomization study

Konstantinos K. Tsilidis*, Nikos Papadimitriou, Niki Dimou, Dipender Gill, Sarah J. Lewis, Richard M. Martin, Neil Murphy, Georgios Markozannes, Verena Zuber, Amanda J. Cross, Kimberley Burrows, David S. Lopez, Timothy J. Key, Ruth C. Travis, Aurora Perez-Cornago, David J. Hunter, Fränzel J.B. Van Duijnhoven, Demetrius Albanes, Volker Arndt, Sonja I. BerndtStéphane Bézieau, Timothy Bishop, Juergen Boehm, Hermann Brenner, Andrea Burnett-Hartman, Peter T. Campbell, Graham Casey, Sergi Castellví-Bel, Andrew T. Chan, Jenny Chang-Claude, Albert De La Chapelle, Jane C. Figueiredo, Steven J. Gallinger, Graham G. Giles, Phyllis J. Goodman, Andrea Gsur, Jochen Hampe, Heather Hampel, Michael Hoffmeister, Mark A. Jenkins, Temitope O. Keku, Sun Seog Kweon, Susanna C. Larsson, Loic Le Marchand, Christopher I. Li, Li Li, Annika Lindblom, Vicente Martín, Roger L. Milne, Victor Moreno

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

25 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)1490-1502
Number of pages13
JournalAmerican Journal of Clinical Nutrition
Issue number6
Publication statusPublished - 1 Jun 2021


  • colorectal cancer
  • genes
  • Mendelian randomization
  • nutrition
  • supplements


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