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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

European Journal of Human Genetics volume 32, pages 155–162 (2024)Cite this article

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Abstract

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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Fig. 1: Overview of purine metabolism and mechanism of action of allopurinol.
Fig. 2: Overview of folate metabolism and mechanism of action of methotrexate.

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Data availability

All data and material are either included in the supplementary information or publicly available (i.e., the published articles, PubMed). The guidelines and background information are available on KNMP.nl [1] and will be available on PharmGKB.org.

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Acknowledgements

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.

Funding

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)’.

Author information

Author notes

  1. These authors jointly supervised this work: Elisa J. F. Houwink, Gerard A. Rongen.

Authors and Affiliations

  1. Department of Pharmacology and Toxicology, Radboud University Medical Centre, Nijmegen, The Netherlands

    Karel H. van der Pol & Gerard A. Rongen

  2. Royal Dutch Pharmacists Association (KNMP), The Hague, The Netherlands

    Marga Nijenhuis & Bianca Soree

  3. Pharmacy Boterdiep, Groningen, The Netherlands

    Nienke J. de Boer-Veger

  4. Pharmacy De Katwijkse Apotheek, Katwijk, The Netherlands

    Anne Marie Buunk

  5. Department of Clinical Pharmacy & Toxicology, Leiden University Medical Center, Leiden, The Netherlands

    Henk-Jan Guchelaar & Jesse J. Swen

  6. Department of Clinical Pharmacy, Wilhelmina Hospital, Assen, The Netherlands

    Arne Risselada

  7. Department of Clinical Chemistry, Erasmus University Medical Center, Rotterdam, The Netherlands

    Ron H. N. van Schaik

  8. University of Groningen, Groningen Research Institute of Pharmacy, Department of PharmacoTherapy, -Epidemiology and -Economy, Groningen, The Netherlands

    Daan Touw

  9. Department of Clinical Chemistry, St. Jansdal Hospital, Harderwijk, The Netherlands

    Jan van der Weide

  10. Parnassia Psychiatric Institute/PsyQ, Amsterdam, The Netherlands

    Roos van Westrhenen

  11. Department of Psychiatry & Neuropsychology, Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, The Netherlands

    Roos van Westrhenen

  12. Institute of Psychiatry, Psychology & Neuroscience, King’s College London, London, UK

    Roos van Westrhenen

  13. Department of Clinical Pharmacy, Division Laboratories, Pharmacy and Biomedical Genetics, University Medical Centre Utrecht, Utrecht, The Netherlands

    Vera H. M. Deneer

  14. Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences (UIPS), Department of Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands

    Vera H. M. Deneer

  15. Department of Public Health and Primary Care (PHEG), Leiden University Medical Center, Leiden, The Netherlands

    Elisa J. F. Houwink

  16. Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands

    Gerard A. Rongen

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  1. Karel H. van der Pol
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Contributions

KP drafted the manuscript and contributed to interpretation of results. EH and GR supervised drafting of the manuscript and contributed to conceiving the work and interpretation of the results. MN contributed to conceiving the work and interpretation of the results, and performed the data extraction. BS drafted and published English versions of clinical decision support texts. NBV, AB, HG, AR, RS, JS, DT, JW, RW, and VD contributed to conceiving the work and interpretation of the results. In addition, all authors revised the manuscript and approved the final version as well as agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Corresponding author

Correspondence to Marga Nijenhuis.

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Competing interests

The authors declare no competing interests.

Ethical approval

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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Supplementary information

Supplementary Material 1. search terms

Supplementary Table 1. literature review of ABCG2-allopurinol

Supplementary Table 2. literature review of HLA-allopurinol

Supplementary Table 3. literature review of MTHFR-methotrexate

Supplementary Table 4. literature review of MTHFR-folic acid

Supplementary Table 5. allele frequencies

Supplementary Table 6. Dutch Pharmacogenetics Working Group guideline for ABCG2-allopurinol

Supplementary Table 7. Dutch Pharmacogenetics Working Group guideline for HLAB5801

Supplementary Table 8.Dutch Pharmacogenetics Working Group guideline for MTHFR-methotrexate

Supplementary Table 9. Dutch Pharmacogenetics Working Group guideline for MTHFR-folic acid

Supplementary Table 10. suggested clinical decision support texts for ABCG2-allopurinol

Supplementary Table 11. suggested clinical decision support texts for HLA

Supplementary Table 12. suggested clinical decision support texts for MTHFR-methotrexate

Supplementary Table 13. suggested clinical decision support texts for MTHFR-folic acid

Supplementary Table 14. genotype to predicted phenotype translation

Supplementary Table 15. clinical implication scores

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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 32, 155–162 (2024). https://doi.org/10.1038/s41431-022-01180-0

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