Association of the TYMS 3G/3G genotype with poor response and GGH 354GG genotype with the bone marrow toxicity of the methotrexate in RA patients

Jekic, Biljana; Lukovic, Ljiljana; Bunjevacki, Vera; Milić, Vera; Novaković, Ivana; Damnjanovic, Tatjana; Milašin, Jelena; Popović, Branka; Maksimović, Nela; Damjanov, Nemanja; Radunović, Goran; Kovacevic, Ljiljana; Krajinović, Maja

doi:10.1007/s00228-012-1341-3

Cited by 49 publications

(38 citation statements)

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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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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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“…It has been observed that carriers of a double 28-bp tandem repeat in the TS promoter exhibit lower TS gene expression and activity than those with triple 28-bp repeats [35]. Several studies exploring potential influence of TS 5′UTR repeats on MTX toxicity and efficacy in RA patients found patients homozygous for TS 5′UTR 3R allele required higher MTX dose and had poor response to MTX as compared with those with at least one 2R [23,36,37]. When 2R/2R genotype was incorporated in toxicogenetic index together with several other folate cycle polymorphisms, significant correlation with toxicity to MTX was seen [25].…”

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

confidence: 99%

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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“…El genotipo no TT de GGH T16 C (rs1800909) se asoció con mayor riesgo de disfunción hepática y el polimorfismo-354 T GGH-G se relacionó con mayor riesgo de mielosupresión 20,22 .…”

Section: Características Poblacionales Polimorfismos Y Genotiposunclassified

“…Los PMF en el gen que codifica esta enzima incluye repetición en tándem (dos o tres repeticiones de una unidad de 28 pb) en la región potenciadora en el 5'-UTR. Los pacientes homocigotos para la triple (3R) repetición de alelo de TYMS, presentan aumento en la expresión ARNm TYMS y mayor actividad enzimática en comparación con aquellos con el alelo 2R 22 .…”

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Farmacogenética del metotrexato en artritis reumatoide. Revisión sistemática

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Londoño

et al. 2016

Revista Colombiana de Reumatología

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Association of the TYMS 3G/3G genotype with poor response and GGH 354GG genotype with the bone marrow toxicity of the methotrexate in RA patients

Abstract: The 3 G/3 G genotype of the TYMS gene may indicate predisposition of poor response to MTX and GG genotype of GGH -354 T > G polymorphism may have high predictive value for myelosuppression in RA patients.

Cited by 49 publications

References 34 publications

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

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

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

Farmacogenética del metotrexato en artritis reumatoide. Revisión sistemática

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