Polymorphisms in the methylenetetrahydrofolate reductase gene were associated with both the efficacy and the toxicity of methotrexate used for the treatment of rheumatoid arthritis, as evidenced by single locus and haplotype analyses

Abstract

5,10-Methylenetetrahydrofolate reductase (MTHFR), a key enzyme involved in folate metabolism, has two common polymorphisms that affect enzyme activity. The objective of this study was to examine whether there was a correlation between the genotype or haplotype of the MTHFR gene and the efficacy or toxicity of methotrexate (MTX) in the treatment of rheumatoid arthritis. MTX-treated rheumatoid arthritis patients (n = 106) were selected from outpatient clinics and used for a retrospective study to examine the correlation between genotypes or haplotypes concerning polymorphisms of the MTHFR gene, and the efficacy or toxicity of MTX. Estimation of the haplotype frequencies was performed by maximum likelihood estimation based on expectation maximization algorithm. Single locus analysis examining each locus separately showed that patients with 1298C were receiving significantly lower doses of MTX compared to patients without [P < 0.05, relative risk (RR) = 2.18, 95% confidence interval (CI) 1.17-4.06], while a higher rate of overall MTX toxicity was observed in patients with 677T than those without (P < 0.05, RR = 1.25, 95% CI 1.05-1.49). An estimation of haplotype frequencies showed that there was no 677T-1298C haplotype in the population. Posterior distribution of the diplotype configuration for each individual was concentrated on a single configuration. Patients with the 677C-1298C haplotype were receiving lower doses of MTX than those without (P < 0.05, RR = 2.14, 95% CI 1.13-4.07), while subjects with 677T-1298A had a higher frequency of side-effects from MTX (P < 0.05, RR = 1.42, 95% CI 1.11-1.82). Both single locus and haplotype analyses suggest that polymorphisms within the MTHFR gene are associated with both the efficacy and toxicity of MTX in rheumatoid arthritis patients. Pharmacokinetic studies are necessary to prove the association.

Role of polymorphisms in MTHFR and MTHFD1 genes in the outcome of childhood acute lymphoblastic leukemia

“…15 Increased MTX toxicity was also noted in ovarian cancer patients with the TT677 genotype, 28 and in patients with rheumatoid arthritis who were carriers of the T677A1298 haplotype. 16 MTX-associated effects observed in these studies were suggested to arise due to low 5-methyl-THF levels associated with the T677 variant.…”

“…Individuals with the C677A1298 or C677C1298 haplotypes appeared protected from the event, suggesting, at least in our study, that the C1298 variant has little influence on ALL outcome. The association of the MTHFR C1298 variant with parameters of MTX sensitivity was less frequently studied than that of T677, and so far has been assessed only in studies of rheumatoid arthritis, among which one study showed that patients with the C677C1298 haplotype responded better to the MTX treatment, 16 while in another study no influence of any of the MTHFR polymorphisms was observed. 29 With regard to the MTHFD1 polymorphism, its functional role in folate pool maintenance has been suggested: women with the MTHFD1 AA1958 genotype were found to be at an increased risk of having NTD-affected offspring.…”

“…11,12 Recently, the potential role of these polymorphisms in response to MTX treatment has been addressed in several studies. [13][14][15][16] Higher in vitro MTX sensitivity of a patient's lymphoblasts with the TT677 genotype has been shown. 13 Likewise, among adult acute lymphoblastic leukemia (ALL) and chronic myelogenic leukemia (CML) patients receiving MTX, higher drug toxicity was observed in TT677 homozygotes as compared to individuals with other MTHFR genotypes.…”

Vaccination and autoimmune diseases: is prevention of adverse health effects on the horizon?

“…The MTHFR 677 variant has been associated with many phenotypes, including cardiovascular function, transplant health, toxicity of immunosuppressive drugs, and systemic inflammation [152,153]. Elevated plasma homocysteine levels stimulate endothelial inflammatory responses, which could contribute to adverse events.…”

Association of methotrexate effects and single‐nucleotide polymorphisms in the folate pathway in rheumatoid arthritis: Comment on the article by Wessels et al

“…Through direct inhibition of DHFR, MTX influences the adequacy of the intracellular reduced folate pools and thereby has effects on the activity of MTHFR. Indeed, as Wessels et al state, there is published literature demonstrating the effects of SNPs in the MTHFR gene on the efficacy and toxicity of MTX in RA (7)(8)(9). RFC (also called SLC19A1), a member of the solute carrier family of transporters, mediates the transport of reduced folates into the cell by an energy-dependent process.…”