MTHFR gene polymorphisms and outcome of methotrexate treatment in patients with rheumatoid arthritis: analysis of key polymorphisms and meta-analysis of C677T and A1298C polymorphisms

Abstract

Association of two key variants mapping to the MTHFR gene (C677T (rs1801133) and A1298C (rs1801131)) with response to methotrexate (MTX) remains controversial. We investigated these and other markers spanning the gene as predictors of MTX efficacy and adverse events in a UK rheumatoid arthritis (RA) patient cohort and performed a meta-analysis of the two key variants using all published data. The tagging single nucleotide polymorphisms (SNPs) were genotyped in 309 patients with well-defined outcomes to MTX treatment and 17 studies were included in the metaanalysis. No association of the SNPs tested was detected with MTX efficacy or toxicity in our UK cohort. After combining our data with previous studies by meta-analysis, the random effects pooled odds ratios (OR) for both C677T and A1298C showed no association with efficacy or toxicity for either of the SNPs (efficacy: OR ¼ 1.05 (95% confidence interval (CI) 0.83-1.32) and OR ¼ 0.81 (95% CI 0.53-1.24), respectively; toxicity: OR ¼ 1.38 (95% CI 0.90-2.12) and OR ¼ 1.19 (95% CI 0.80-1.78), respectively). The available evidence suggests that the MTHFR C677T and A1298C gene polymorphisms are not reliable predictors of response to MTX treatment in RA patients.

Folate Metabolic Pathway Single Nucleotide Polymorphisms: A Predictive Pharmacogenetic Marker of Methotrexate Responsel in Indian (Asian) Patients with Rheumatoid Arthritis

“…Similar to our result, Dutch and Japanese RA cohorts showed association of MTHFR 1298 A allele with greater clinical improvement with MTX [39,40]. However, comparable to other studies [41,42] we report negative association of these SNPs with MTX-related toxicity in our RA population. The RFC1 80G/A nonsynonymous SNP rs1051266 results in substitution of arginine for histidine at codon 27 at the first transmembrane domain of the RFC1 protein [43] and may affect MTX transport into the cell and thus intracellular MTX-PG levels [24].…”

Low expression of CD39 on regulatory T cells as a biomarker for resistance to methotrexate therapy in rheumatoid arthritis

“…Polymorphisms in the SCL19A1 (solute carrier family 19, member 1) gene encoding the protein folate transporter 1 have also been described to implicate the therapeutic efficacy of the MTX (28). However, subsequent investigations produced conflicting results (29,30). Thus, the mechanisms of, and functional biomarker for, the development of MTX resistance remains poorly understood (31).…”

MTHFR Functional Genetic Variation and Methotrexate Treatment Response in Rheumatoid Arthritis: A Meta-Analysis

“…Individuals carrying the TT genotype of rs1801133 have been shown to have increased plasma homocysteine levels, but this is not exacerbated by carriage of the minor C allele of rs1801131 [9]. Studies investigating the role of these two SNPs in the context of MTX treatment have largely focused on their impact on AEs, including several meta-analyses [11][12][13]. To date three meta-analyses have been published on MTX response and MTHFR SNPs using heterogeneous outcome measures and including small, underpowered, studies [11,12,14].…”

“…Studies investigating the role of these two SNPs in the context of MTX treatment have largely focused on their impact on AEs, including several meta-analyses [11][12][13]. To date three meta-analyses have been published on MTX response and MTHFR SNPs using heterogeneous outcome measures and including small, underpowered, studies [11,12,14]. Owen et al combined data from ten studies, which included American College of Rheumatology (ACR)20 and European League Against Rheumatism (EULAR) criteria, and MTX dose as measures of response, among others [12].…”