Influence of polymorphisms within the methotrexate pathway genes on the toxicity and efficacy of methotrexate in patients with juvenile idiopathic arthritis

Abstract

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Methotrexate (MTX), which causes adverse effects, such as liver and/or renal dysfunction, is the most common disease‐modifying antirheumatic drug used for the treatment of rheumatoid arthritis and articular‐type juvenile idiopathic arthritis (JIA). • Pharmacogenetic studies analysing the MTX pathway genes would aid in the development of more personalized therapy. • Results regarding the influence of gene polymorphisms on the toxicity and efficacy of MTX are conflicting, and there are marked differences between racial groups in pharmacogenetics. WHAT THIS STUDY ADDS • The non‐TT genotype at γ‐glutamyl hydrolase (GGH) T16C is associated with a high risk of liver dysfunction due to MTX, even after adjustment for duration of MTX treatment. • Longer time interval from disease onset to MTX treatment and rheumatoid factor positivity are associated with lower efficacy of MTX in Japanese patients, as reported previously in Caucasian patients with JIA. AIMS We investigated whether several polymorphisms within the methotrexate (MTX) pathway genes were related to the toxicity and efficacy of MTX in 92 Japanese patients with articular‐type juvenile idiopathic arthritis (JIA). METHODS Eight gene polymorphisms within the MTX pathway genes, namely, RFC, BCRP, MTHFR (two), FPGS, γ‐glutamyl hydrolase (GGH; two) and ATIC, were genotyped using TaqMan assays. Liver dysfunction was defined as an increase in alanine transaminase to five times the normal upper limit. Non‐responders to MTX were defined as patients refractory to MTX and were therefore treated with biologics. RESULTS The non‐TT genotype at GGH T16C was associated with a high risk of liver dysfunction (P = 0.028, odds ratio = 6.90, 95% confidence interval 1.38–34.5), even after adjustment for the duration of MTX treatment. A longer interval from disease onset to treatment (8.5 and 21.3 months, P = 0.029) and rheumatoid factor positivity (P = 0.026, odds ratio = 2.87, 95% confidence interval 1.11–7.39) were associated with lower efficacy of MTX. CONCLUSIONS The non‐TT genotype at GGH T16C was associated with a high risk of liver dysfunction, presumably because the C allele of GGH C16T may reduce the activity of GGH. The time interval before MTX treatment and rheumatoid factor positivity were associated with the efficacy of MTX treatment. The pharmacogenetics of the MTX pathway genes affects the toxicity and efficacy of MTX in Japanese JIA patients.

γ-Glutamyl hydrolase modulation significantly influences global and gene-specific DNA methylation and gene expression in human colon and breast cancer cells

“…High GGH expression was shown to be associated with a higher risk of developing advanced toxicity to pemetrexed, a multi-targeted antifolate, in patients with advanced breast cancer (Llombart-Cussac et al 2007). Furthermore, several recently identified and characterized functionally significant genetic and epigenetic polymorphisms of GGH have been reported to predict response to and toxicity of antifolate-based treatment in patients with several cancers (Cheng et al 2004;Kim et al 2008;Koomdee et al 2012;Silva et al 2013;Smit et al 2012;Wang et al 2014) and inflammatory arthritis (Dervieux et al 2004;Hayashi et al 2009;Jekic et al 2013;Owen et al 2012;van der Straaten et al 2007;Yanagimachi et al 2011). Our data herein provide evidence that GGH modulation significantly influences expression and CpG DNA methylation of genes involved in important biological pathways that might account for the observed effects of GGH modulation on cancer risk, prognosis, and treatment response.…”

Methotrexate Pharmacokinetic Genetic Variants are Associated with Outcome in Rheumatoid Arthritis Patients

“…No significant associations between genetic variants and outcome were found in two studies in Caucasian RA patients [28,29] or in a Japanese study that included patients with articular-type juvenile idiopathic arthritis [30]. Two recent publications have suggested that the FPGS is involved in the MTX outcome.…”

Pediatric Perspective on Pharmacogenomics

“…The influence of these polymorphisms on the toxicity and efficacy of MTX is conflicting and there are differences between ethnic groups [32,73]. MTX treatment may also be affected by child development, which may be a predictive factor in pediatric rheumatology [74].…”

“…The influence of polymorphisms within the MTX pathway genes on the toxicity and efficacy of therapy in patients with rheumatoid arthritis and JIA has been studied [70]. Several SNP associations (p-value trend ≤ 0.05) [71] in MTX pathway genes (encoding for SLC19A1 and SLC16A7, MTHFR, GGH, ATIC and BCRP/ABCG2) in patients with JIA have been reported [71][72][73][74][75]. In particular, the GGH gene involved in MTX metabolism with a specific genotype (the non-TT genotype at GGH T16C) was found to be associated with a high risk of liver dysfunction (p = 0.028, OR: 6.90, 95% CI: 1.38-34.5) [73].…”