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Genetically proxied ketohexokinase function and risk of colorectal cancer: a Mendelian randomisation study
  1. Amée M Buziau1,2,3,
  2. Philip J Law4,
  3. Gabriella Blokland5,
  4. Casper Schalkwijk2,3,
  5. Jean Scheijen2,3,
  6. Pomme Simons1,2,3,
  7. Carla van der Kallen2,6,
  8. Simone Eussen2,7,8,
  9. Pieter C Dagnelie2,6,
  10. Marleen van Greevenbroek2,3,
  11. Richard S Houlston4,
  12. Anke Wesselius9,10,
  13. Molly Went4,
  14. Coen Stehouwer2,6,
  15. Martijn CGJ Brouwers1,2
  1. 1 Department of Internal Medicine, division of Endocrinology and Metabolic Disease, Maastricht University Medical Centre, Maastricht, The Netherlands
  2. 2 CARIM School for Cardiovascular disease, Maastricht University, Maastricht, The Netherlands
  3. 3 Department of Internal Medicine, Division of General Internal Medicine, Laboratory for Metabolism and Vascular Medicine, Maastricht University, Maastricht, The Netherlands
  4. 4 Division of Genetics and Epidemiology, The Institute of Cancer Research, London SW7 3RP, UK
  5. 5 Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht University, Maastricht, The Netherlands
  6. 6 Department of Internal Medicine, Maastricht University Medical Centre, Maastricht, The Netherlands
  7. 7 Department of Epidemiology, Maastricht University, Maastricht, The Netherlands
  8. 8 CAPHRI Care and Public Health Research Institute, Maastricht University, Maastricht, The Netherlands
  9. 9 NUTRIM School for Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, The Netherlands
  10. 10 Department of Complex Genetics and Epidemiology, Maastricht University, Maastricht, The Netherlands
  1. Correspondence to Professor Martijn CGJ Brouwers, Maastricht University Medical Centre+, Maastricht, The Netherlands; mcgj.brouwers{at}mumc.nl

https://doi.org/10.1136/gutjnl-2021-326299

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    We read with interest the findings from the longitudinal study by Hur et al showing that a high consumption of sugar sweetened beverages in adulthood is associated with early-onset colorectal cancer (CRC).1 However, attractive the association, the authors acknowledge that their finding does not establish a causal relationship since residual confounding cannot be excluded.

    Biological plausibility for a causal role of fructose, one of the principal added sugars, in the pathogenesis of CRC has recently been provided by Taylor et al, who demonstrated a direct link between fructose 1-phosphate (F1-P) and intestinal tumour growth in mice (figure 1A).2

    Figure 1

    (A) After intestinal absorption, fructose is phosphorylated by ketohexokinase. Fructose 1-phosphate (F1P) inhibits the M2 isoform of pyruvate kinase (PKM2) by formation of inactive PKM2 monomers, which enhances hypoxic cell survival and, consequently, intestinal tumour growth.2 It is hypothesised that a common missense variant in the ketohexokinase gene (rs2306481) results in impaired fructose phosphorylation and, hence, protection from colorectal carcinoma (green arrows). Furthermore, it is anticipated that the unphosphorylated fructose will escape metabolism and will subsequently be excreted via the kidneys in the urine, similar to essential fructosuria, an inborn error of metabolism.5 (B) The rs2306481 A allele is associated with greater 24 hours urinary fructose excretion …

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    Footnotes

    • Contributors AMB and MCGJB: conception or design of the work. CGS, JLJMS, CJHK, SJPME, PCD, MMJG, AW, CDAS, PL and RH: acquisition. GAMB, PL, PIHGS, RH and MW: analysis. AMB, MCGJB, CGS, JLJMS, CJHK, SJPME, PCD, MMJG, AW, CDAS, GAMB, PL, PIHGS, RH and MW: interpretation of data. AMB, MCGJB, CGS, JLJMS, CJHK, SJPME, PCD, MMJG, AW, CDAS, GAMB, PL, PIHGS, RH, MW: draft and/or revision of the manuscript.

    • Funding This study was supported by the Dutch Diabetes Research Foundation (personal grant #2017.82.004 to MCGJB). The Maastricht Study was supported by the European Regional Development Fund via OP-Zuid, the Province of Limburg, the Dutch Ministry of Economic Affairs (grant 31O.041), Stichting De Weijerhorst (Maastricht, the Netherlands), the Pearl String Initiative Diabetes (Amsterdam, the Netherlands), School for Cardiovascular Diseases (CARIM, Maastricht, the Netherlands), School for Public Health and Primary Care (CAPHRI, Maastricht, the Netherlands), School for Nutrition and Translational Research in Metabolism (NUTRIM, Maastricht, the Netherlands), Stichting Annadal (Maastricht, the Netherlands), Health Foundation Limburg (Maastricht, the Netherlands), and by unrestricted grants from Janssen-Cilag B.V. (Tilburg, the Netherlands), Novo Nordisk Farma B.V. (Alphen aan den Rijn, the Netherlands), Sanofi-Aventis Netherlands B.V. (Gouda, the Netherlands) and Medtronic (Tolochenaz, Switzerland).

    • Competing interests None declared.

    • Provenance and peer review Not commissioned; externally peer reviewed.

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