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

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.

Fig. 1. Overview of purine metabolism and mechanism of action of allopurinol.

Rectangles represent substances in purine metabolism pathway; ovals represent enzymes; lines originating from allopurinol represent enzyme inhibition by allopurinol; PNP purine nucleoside phosphorylase; AD adenosine deaminase; GD guanine deaminase; XO xanthine oxidase.

Fig. 2. Overview of folate metabolism and mechanism of action of methotrexate.

Rectangles with continous borders represent substances in the folic acid cycle; rectangles with dotted borders represent substances in the methionine cycle; rectangles with dashed borders represent substances needed for DNA synthesis; ovals with continous borders represent enzymes; ovals with dashed borders represent cofactors; lines originating from methotrexate represent enzyme inhibition by methotrexate; B12 vitamin B12; DHFR dihydrofolate reductase; MS methionine synthase; SHMT serine hydroxymethyltransferase; TS thymidylate synthase.