Genetic polymorphisms in folate pathway enzymes as a possible marker for predicting the outcome of methotrexate therapy in Japanese patients with rheumatoid arthritis

Hayashi, Hideki; Fujimaki, Chihiro; Daimon, T.; Tsuboi, Seiji; Matsuyama, Taiji; Itoh, Ken

doi:10.1111/j.1365-2710.2009.01046.x

Cited by 51 publications

(31 citation statements)

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“…Supporting this observation studies in RA patients have found correlation between GGH 401T allele with reduced efficacy [34] and lower MTXPG accumulation [24]. We observed GGH 401TT was associated with hepatic and overall AE in our RA patients.…”

Section: Effect Of Snps In Folate Metabolism On Mtx Response Researchsupporting

confidence: 77%

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

et al. 2015

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Aim:We evaluated the pharmacogenetic influence of genetic polymorphisms in folate pathway genes in Indian rheumatoid arthritis patients receiving methotrexate (MTX). Patients & methods: Twelve polymorphisms within nine folate pathway genes were analyzed for association with MTX response in 322 Indian rheumatoid arthritis (RA) patients and MTX pharmacokinetics in 94 RA patients. Results: Polymorphisms in GGH, SHMT1 and TS were associated with MTX-related adverse events while SNPs in MTHFR and RFC1/SLC19A1 were associated with MTX efficacy. TS5′UTR and SHMT1 polymorphisms were associated with higher plasma levels of MTX. Conclusion: Polymorphisms in folate-MTX pathway genes contribute to MTX response and affect MTX concentrations in Indian RA patients. A toxicogenetic index could identify patients who develop adverse events to MTX. Keywords: folate metabolism • homocysteine • Indians • methotrexate • pharmacogenomics • pharmacokineticsMethotrexate (MTX) a folic acid analog, is a first-line treatment and is the most commonly prescribed disease modifying antirheumatic drug (DMARD) for the treatment of rheumatoid arthritis (RA). It is also a key drug in most combination therapies, and a gold standard for comparing new therapies for RA. MTX is also frequently used in the management of other forms of inflammatory arthritis [1]. The efficacy and toxicity profile of MTX has been well proven in various randomized controlled trials and longitudinal cohort studies [2]; however, its use is confounded by unpredictable interpatient variability in clinical response and toxicity. Approximately 60% of patients experience good clinical response and 30% discontinue therapy due to adverse events [3][4][5]. Clinicians face challenges in predicting adequate disease control and adverse events in patients receiving MTX. Due to the inability to predict MTX response (efficacy and toxicity), regular blood monitoring is required in these patients. Further, additional DMARDs or costly biologic therapies are needed for MTX nonresponders. Thus MTX therapy in RA is a dynamic process and requires subtle balance between benefits and risk, and there is a great need for better predictive markers for MTX efficacy and toxicity.The therapeutic effectiveness and cytotoxicity of folate antagonists are both due to their inhibition of DNA and RNA synthesis. Folate metabolism is the major target of MTX (Figure 1). However, the exact mechanism by which MTX modulates inflammation in RA is still unclear. It is thought that the antiinflammatory effects mediated by adenosine release may be more important than the antiproliferative effects [6,7] future science groupResearch Article Ghodke-Puranik, Puranik, Shintre et al.thesis such as 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) transformylase (ATIC) and GART. This causes accumulation of adenosine, which has antiinflammatory activity [7]. Other folate enzymes, such as mehthylenetetrahydrofolate reductase (MTHFR), serine hydroxymethyltransferase 1 (SHMT) and enzymes in the one carbon pool [methionine sy...

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Section: Effect Of Snps In Folate Metabolism On Mtx Response Researchsupporting

confidence: 77%

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

et al. 2015

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“…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.…”

Section: Discussionsupporting

confidence: 54%

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

et al. 2014

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c-Glutamyl hydrolase (GGH) plays an important role in folate homeostasis by catalyzing hydrolysis of polyglutamylated folate into monoglutamates. Polyglutamylated folates are better substrates for several enzymes involved in the generation of S-adenosylmethionine, the primary methyl group donor, and hence, GGH modulation may affect DNA methylation. DNA methylation is an important epigenetic determinant in gene expression, in the maintenance of DNA integrity and stability, and in chromatin modifications, and aberrant or dysregulation of DNA methylation has been mechanistically linked to the development of human diseases including cancer. Using a recently developed in vitro model of GGH modulation in HCT116 colon and MDA-MB-435 breast cancer cells, we investigated whether GGH modulation would affect global and gene-specific DNA methylation and whether these alterations were associated with significant gene expression changes. In both cell lines, GGH overexpression decreased global DNA methylation and DNA methyltransferase (DNMT) activity, while GGH inhibition increased global DNA methylation and DNMT activity. Epigenomic and gene expression analyses revealed that GGH modulation influenced CpG promoter DNA methylation and gene expression involved in important biological pathways including cell cycle, cellular development, and cellular growth and proliferation. Some of the observed altered gene expression appeared to be regulated by changes in CpG promoter DNA methylation. Our data suggest that the GGH modulation-induced changes in total intracellular folate concentrations and content of long-chain Electronic supplementary material The online version of this article

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“…Data from 27 studies investigating MTHFR SNPs and MTX related efficacy and toxicity in RA patients were initially identified through the database searches [18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][45][46][47][48][49][50][51][52][53][54] and combined with results from our study, leaving 28 studies for review. From these, 11 studies were excluded due to lack of available data, leaving 17 studies including the present study published between 2001 and 2010 meeting the eligibility criteria, which were included in the meta-analysis: [18][19][20][22][23][24][25][26][27][28]32,33,45,46,53,54 For the C677T SNP, 10 studies were included for the efficacy analysis and 13 studies for the toxicity analysis (Table 2) and for the A1298C SNP 8 studies were included for the efficacy analysis and 8 studies for the toxicity analysis (Table 3).…”

Section: Meta-analysis: Studies Includedmentioning

confidence: 99%

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

et al. 2011

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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.

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Genetic polymorphisms in folate pathway enzymes as a possible marker for predicting the outcome of methotrexate therapy in Japanese patients with rheumatoid arthritis

Abstract: Patients with RA having RFC 80A and GGH-401T alleles were less responsive to MTX than those with RFC 80A and without GGH-401T alleles. Thus, this data may be useful for guiding treatment of RA patients with MTX.

Cited by 51 publications

References 34 publications

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

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

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

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

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