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Dutch pharmacogenetics working group guideline for the gene-drug interaction of ABCG2, HLA-B and Allopurinol, and MTHFR, folic acid and methotrexate.

  • van der Pol, Karel H1
  • Nijenhuis, Marga2
  • Soree, Bianca3
  • de Boer-Veger, Nienke J4
  • Buunk, Anne Marie5
  • Guchelaar, Henk-Jan6
  • Risselada, Arne7
  • van Schaik, Ron H N8
  • Swen, Jesse J6
  • Touw, Daan9
  • van der Weide, Jan10
  • van Westrhenen, Roos11, 12, 13
  • Deneer, Vera H M14, 15
  • Houwink, Elisa J F16
  • Rongen, Gerard A1, 17
  • 1 Department of Pharmacology and Toxicology, Radboud University Medical Centre, Nijmegen, The Netherlands. , (Netherlands)
  • 2 Royal Dutch Pharmacists Association (KNMP), The Hague, The Netherlands. [email protected]. , (Netherlands)
  • 3 Royal Dutch Pharmacists Association (KNMP), The Hague, The Netherlands. , (Netherlands)
  • 4 Pharmacy Boterdiep, Groningen, The Netherlands. , (Netherlands)
  • 5 Pharmacy De Katwijkse Apotheek, Katwijk, The Netherlands. , (Netherlands)
  • 6 Department of Clinical Pharmacy & Toxicology, Leiden University Medical Center, Leiden, The Netherlands. , (Netherlands)
  • 7 Department of Clinical Pharmacy, Wilhelmina Hospital, Assen, The Netherlands. , (Netherlands)
  • 8 Department of Clinical Chemistry, Erasmus University Medical Center, Rotterdam, The Netherlands. , (Netherlands)
  • 9 University of Groningen, Groningen Research Institute of Pharmacy, Department of PharmacoTherapy, -Epidemiology and -Economy, Groningen, The Netherlands. , (Netherlands)
  • 10 Department of Clinical Chemistry, St. Jansdal Hospital, Harderwijk, The Netherlands. , (Netherlands)
  • 11 Parnassia Psychiatric Institute/PsyQ, Amsterdam, The Netherlands. , (Netherlands)
  • 12 Department of Psychiatry & Neuropsychology, Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, The Netherlands. , (Netherlands)
  • 13 Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK.
  • 14 Department of Clinical Pharmacy, Division Laboratories, Pharmacy and Biomedical Genetics, University Medical Centre Utrecht, Utrecht, The Netherlands. , (Netherlands)
  • 15 Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences (UIPS), Department of Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands. , (Netherlands)
  • 16 Department of Public Health and Primary Care (PHEG), Leiden University Medical Center, Leiden, The Netherlands. , (Netherlands)
  • 17 Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands. , (Netherlands)
Published Article
European Journal of Human Genetics
Springer Nature
Publication Date
Feb 01, 2024
DOI: 10.1038/s41431-022-01180-0
PMID: 36056234


The Dutch Pharmacogenetics Working Group (DPWG) aims to facilitate PGx implementation by developing evidence-based pharmacogenetics guidelines to optimize pharmacotherapy. This guideline describes the gene-drug interaction of ABCG2 with allopurinol, HLA-B with allopurinol, MTHFR with folic acid, and MTHFR with methotrexate, relevant for the treatment of gout, cancer, and rheumatoid arthritis. A systematic review was performed based on which pharmacotherapeutic recommendations were developed. Allopurinol is less effective in patients with the ABCG2 p.(Gln141Lys) variant. In HLA-B*58:01 carriers, the risk of severe cutaneous adverse events associated with allopurinol is strongly increased. The DPWG recommends using a higher allopurinol dose in patients with the ABCG2 p.(Gln141Lys) variant. For HLA-B*58:01 positive patients the DPWG recommends choosing an alternative (for instance febuxostat). The DPWG indicates that another option would be to precede treatment with allopurinol tolerance induction. Genotyping of ABCG2 in patients starting on allopurinol was judged to be 'potentially beneficial' for drug effectiveness, meaning genotyping can be considered on an individual patient basis. Genotyping for HLA-B*58:01 in patients starting on allopurinol was judged to be 'beneficial' for drug safety, meaning it is advised to consider genotyping the patient before (or directly after) drug therapy has been initiated. For MTHFR-folic acid there is evidence for a gene-drug interaction, but there is insufficient evidence for a clinical effect that makes therapy adjustment useful. Finally, for MTHFR-methotrexate there is insufficient evidence for a gene-drug interaction. © 2022. The Author(s), under exclusive licence to European Society of Human Genetics.

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