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.
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We dedicate this article to Bob Wilffert, who sadly passed away last year. He was a much respected member of our pharmacogenetic working group for many years.
This project has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 668353. The DPWG received funding from the Royal Dutch Pharmacists Association. G.A. Rongen received funding from the ZonMw programme ‘Goed Gebruik Geneesmiddelen’: grant number 848044004 ‘AllopuriNol to treat AtheRosClerosis in patients with Hyperuricemia (ANARCHY)’.
The authors declare no competing interests.
Ethical approval was not required as no individual patient data was used for this article. Data was extracted from other publications and cannot be traced to any individual patient.
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van der Pol, K.H., Nijenhuis, M., Soree, B. et al. Dutch pharmacogenetics working group guideline for the gene-drug interaction of ABCG2, HLA-B and Allopurinol, and MTHFR, folic acid and methotrexate. Eur J Hum Genet (2022). https://doi.org/10.1038/s41431-022-01180-0