Methylene tetrahydrofolate reductase genotypes frequencies: association with the toxicity of and response to methotrexate in rheumatoid arthritis patients

Saleh, Mais; Irshaid, Yacoub M.; Mustafa, Khader N.

doi:10.5414/cp202242

Cited by 17 publications

(9 citation statements)

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“…Many studies showed a lack of association between the two MTHFR gene polymorphism and MTX efficacy [ 20 , 21 , 22 , 23 , 33 , 40 , 42 ], unlike our study. In fact, the A allele of the A1298C polymorphism was significantly associated with a good or moderate EULAR response.…”

Section: Discussioncontrasting

confidence: 99%

“…In our study, the comparison between the genotypic and allelic frequencies of the A1298C SNP, and MTX toxicity did not show any significant difference. The same results were obtained from most studies [ 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 ] such as the English meta-analysis of 2013, which included 17 reports about the MTHFR gene polymorphisms’ influence on MTX toxicity [20] . However, few studies reported an association between this polymorphism and MTX toxicity, with sometimes conflicting results.…”

Section: Discussionsupporting

confidence: 69%

“…Contrarily, the C allele had a protective effect on MTX toxicity in RA patients. Many studies reported the association of the T allele with MTX toxicity [ 17 , 19 , 23 , 25 , 34 , 35 ]. Ranganathan et al reported an association of this allele with alopecia, in African-American RA patients [36] .…”

Section: Discussionmentioning

confidence: 99%

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Association of MTHFR C677T and A1298C gene polymorphisms with methotrexate efficiency and toxicity in Algerian rheumatoid arthritis patients

Berkani¹,

Rahal²,

Allam³

et al. 2017

Heliyon

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Methotrexate (MTX) is the most used drug in rheumatoid arthritis (RA) treatment. However, it shows variability in clinical response, which is explained by an association with genetic polymorphisms. This study aimed to elucidate the role of the two gene polymorphism C677T and A1298C of the methylenetetrahydrofolate reductase (MTHFR) in response to MTX in Algerian RA patients. Study included 54 early RA patient treated with MTX for one year. MTX efficiency and toxicity were evaluated at 6 and 12 months respectively and the two gene polymorphisms were genotyped. No association was found between A1298C polymorphism and MTX toxicity. However, T allele of the C677T polymorphism was associated with the occurrence of MTX adverse effects (p = 0,019, OR: 3,63, 95% CI [1,12 - 12,80]). No association was found between C677T polymorphism and MTX efficiency, while A allele of the A1298C polymorphism was associated with good and moderate response (p = 0,02, OR = 3,28, 95% CI: [1,11– 9,42]). The study of RA biological markers kinetics showed that MTX did not affect antibodies rate unlike inflammatory markers. Our study suggests that MTHFR C677T and A1298C genotyping are associated to MTX toxicity and efficiency, respectively, in RA patients. This offers new perspectives in the personalization of RA treatment in Algeria.

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Section: Discussioncontrasting

confidence: 99%

Section: Discussionsupporting

confidence: 69%

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Association of MTHFR C677T and A1298C gene polymorphisms with methotrexate efficiency and toxicity in Algerian rheumatoid arthritis patients

Berkani¹,

Rahal²,

Allam³

et al. 2017

Heliyon

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“…The most frequent mutations in the MTHFR gene, C677T and especially A1298 C, are associated with a higher toxicity in children and adults treated with high-dose MTX therapy [ 20 , 21 ]. Influence of MTHFR on toxicity in patients treated with low-dose MTX treatment (10–15 mg/m 2 /week) is reported in some populations, but a recent meta-analysis found no clear correlation [ 22 – 24 ]. The C677T and A1298C mutations in the MTHFR gene also lead to higher plasma homocysteine levels, and homocysteine plasma levels have been shown to increase according to the number of mutations in an individual [ 11 ].…”

Section: Discussionmentioning

confidence: 99%

Mutations in the MTHFR gene are not associated with Methotrexate intolerance in patients with juvenile idiopathic arthritis

et al. 2016

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BackgroundMethotrexate (MTX) intolerance is a frequent problem of long-term treatment in juvenile idiopathic arthritis (JIA). Mutations in the methylentetrahydrofolate reductase (MTHFR) gene may increase toxicity of MTX, potentially constituting an initial stimulus for this conditioned response. The objective of this study was to investigate the relationship of common MTHFR gene mutations and occurrence of MTX intolerance in pediatric patients with JIA treated with MTX.MethodsConsecutive JIA patients on at least 3 months of MTX treatment were included in this study. Intolerance to MTX was determined using the Methotrexate Intolerance Severity Score (MISS) questionnaire, and MTX intolerance was defined as MISS values of ≥ 6. Presence of the two most common mutations in the MTHFR gene (C677T and A1298C) was tested using a PCR assay. Results were analyzed using descriptive and non-parametric statistics.Results196 patients were included (73 % female). Of those, 93 (46 %) showed MTX intolerance. 168 patients were genotyped for C677T and A1298C. MTX intolerance was not found to be significantly more frequent among patients with hetero- and homozygous or homozygous mutations C677T or A1298C compared to wild type or heterozygous mutations. Analysis of the correlation between numbers of mutations in these two loci to the MISS score did not yield a statistically significant correlation.ConclusionMutations in the MTHFR gene were not found to be significantly more frequent in JIA patients intolerant to MTX. Toxicity associated with the MTHFR gene seems to result from mechanisms different to those involved in clinical MTX intolerance.Electronic supplementary materialThe online version of this article (doi:10.1186/s12969-016-0071-y) contains supplementary material, which is available to authorized users.

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“…Pharmacogenomics refers to the study of the entire genome (covering transcriptomic and proteomic fields) and the expression levels of individual genes (mRNA) to identify the genetic factors influencing adverse effects and toxicity to MTX treatment. [11] Researchers believe that pharmacogenetic markers may offer a strategy to help identify patients who are more likely to suffer the toxicity of MTX, although this hypothesis requires clinical evidence.…”

Section: Introductionmentioning

confidence: 99%

Polymorphisms and pharmacogenomics for the toxicity of methotrexate monotherapy in patients with rheumatoid arthritis

et al. 2017

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Background:Methotrexate (MTX) is widely used and considered a first-line disease modifying antirheumatic drug (DMARD) for the treatment of rheumatoid arthritis (RA). However, 10% to 30% of patients discontinue therapy within a year of starting the treatment, usually because of undesirable side effects. Many of the relevant genes have been investigated to estimate the association between gene polymorphisms and MTX toxicity in RA patients, although inconsistent results have been reported.Methods:We searched EMBASE and PubMed in February 2016 for polymorphisms and pharmacogenomics study of the toxicity of MTX monotherapy in RA patients. The meta-analysis was stratified by whether genetic variants associated with MTX toxicity.Results:A total of 42 publications that included 28 genes with 88 gene SNPs associated with the transporters, enzymes, and metabolites of MTX or the progression of RA were included in the SR, and 31 studies were included in 7 meta-analyses. The meta-analysis showed a significant association between the toxicity of MTX and the RFC-1 80G > A (rs1051266) polymorphism in the European RA patients.Conclusion:RFC-1 80G > A (rs1051266) polymorphism was associated with MTX toxicity, and larger and more stringent study designs may provide more accurate results for the effect of these SNPs on the MTX toxicity.

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Methylene tetrahydrofolate reductase genotypes frequencies: association with the toxicity of and response to methotrexate in rheumatoid arthritis patients

Abstract: More data from a larger number of RA patients are needed to evaluate the role of pharmacogenetic studies of MTHFR gene in predicting MTX response and toxicity.

Cited by 17 publications

References 0 publications

Association of MTHFR C677T and A1298C gene polymorphisms with methotrexate efficiency and toxicity in Algerian rheumatoid arthritis patients

Association of MTHFR C677T and A1298C gene polymorphisms with methotrexate efficiency and toxicity in Algerian rheumatoid arthritis patients

Mutations in the MTHFR gene are not associated with Methotrexate intolerance in patients with juvenile idiopathic arthritis

Polymorphisms and pharmacogenomics for the toxicity of methotrexate monotherapy in patients with rheumatoid arthritis

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