Outcomes of methotrexate therapy for psoriasis and relationship to genetic polymorphisms

Abstract

Background: The use of methotrexate is limited by interindividual variability in response. Previous studies in patients with either rheumatoid arthritis or psoriasis suggest that genetic variation across the methotrexate metabolic pathway might enable prediction of both efficacy and toxicity of the drug.

Objectives: To assess if single nucleotide polymorphisms (SNPs) across four genes that are relevant to methotrexate metabolism [folypolyglutamate synthase (FPGS), gamma-glutamyl hydrolase (GGH), methylenetetrahydrofolate reductase (MTHFR) and 5-aminoimidazole-4-carboxamide ribonucleotide transformylase (ATIC)] are related to treatment outcomes in patients with psoriasis.

Methods: DNA was collected from 374 patients with psoriasis who had been treated with methotrexate. Data were available on individual outcomes to therapy, namely efficacy and toxicity. Haplotype-tagging SNPs (r(2) > 0.8) for the four genes with a minor allele frequency of > 5% were selected from the HAPMAP phase II data. Genotyping was undertaken using the MassARRAY spectrometric method (Sequenom).

Results: There were no significant associations detected between clinical outcomes in patients with psoriasis treated with methotrexate and SNPs in the four genes investigated.

Conclusions: Genetic variation in four key genes relevant to the intracellular metabolism of methotrexate does not appear to predict response to methotrexate therapy in patients with psoriasis.

Figures

Fig 1

Illustration of some of the key enzymes involved in the metabolism of methotrexate (MTX). MTX is transported into the cell via the solute carrier family 19, member 1 (SLC19A1). It can be actively transported out of the cell by the ATP-binding cassette transporters including ATP-binding cassette, subfamily C (CFTR/MRP), member 1–4 (ABCC1-C4) and ATP-binding cassette, subfamily G, member 2 (ABCG2). Within the cell it undergoes polyglutamation (activation) under the enzymic control of folylpolyglutamate synthase (FPGS). This is a dynamic process where glutamate residues can be removed by gamma-glutamyl hydrolase (GGH). In the polyglutamated form MTX inhibits aminoimidazole-4-carboxamide ribonucleotide transformylase (ATIC), which probably accounts for some of its anti-inflammatory effects via an intracellular rise in adenosine. Inhibition of the folate pathway may not be as important to its mechanism of action in psoriasis, but this pathway includes the enzyme 5,10-methylenetetrahydrofolate reductase (MTHFR) which has been subject to a number of MTX pharmacogenetic studies in the past. MTHFR catalyses the conversion of 5,10-methylenetetrahydrofolate 5,10-CH2-THF to 5-methyltetrahydofolate (5-CH3-THF), which is a cosubstrate for homocysteine remethylation. The polyglutamated form of MTX also inhibits thymidylate synthase (TYMS), which converts deoxyuridylate (dUMP) to deoxythymidylate (dTMP) in the de novo pyrimidine biosynthetic pathway. Genes chosen for this investigation are highlighted in red.