Identification of single nucleotide polymorphisms in the human γ-glutamyl hydrolase gene and characterization of promoter polymorphisms

Chave, Karen J.; Ryan, Thomas J.; Chmura, Stacey E; Galivan, John

doi:10.1016/s0378-1119(03)00807-2

Cited by 76 publications

(46 citation statements)

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“…GGH promoter region may result in increased GGH expression/activity and decreased accumulation of MTXPGs eventually leading to reduced MTX sensitivity or drug resistance [24,32,33]. Supporting this observation studies in RA patients have found correlation between GGH 401T allele with reduced efficacy [34] and lower MTXPG accumulation [24].…”

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

confidence: 82%

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 Researchmentioning

confidence: 82%

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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“…Seventeen SNPs in 13 candidate genes related to the MTX mechanism of action, purine and pyrimidine synthesis (30)(31)(32), were selected, taking into consideration the following criteria (33,34): validated SNP, SNP causes nonsynonymous amino acid change, indications for clinical relevance from previous publications, and a preferred minimal genotype frequency of ϳ10% (20,21,(35)(36)(37)(38)(39)(40)(41)(42)(43)(44)(45)(46)(47)(48).…”

Section: Methodsmentioning

confidence: 99%

A clinical pharmacogenetic model to predict the efficacy of methotrexate monotherapy in recent‐onset rheumatoid arthritis

Wessels

Kooij

Cessie

et al. 2007

Arthritis & Rheumatism

223

152

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Objective. To develop a clinical pharmacogenetic model to predict the efficacy of methotrexate (MTX) in rheumatoid arthritis (RA).Methods. Two hundred five patients with newly diagnosed RA and active disease were treated with MTX (initiated at a dosage of 7.5 mg/week and increased to 15 mg/week after 4 weeks) and folic acid (1 mg/day). If the Disease Activity Score (DAS) was >2.4 at 3 months, the dosage of MTX was increased up to 25 mg/week. Twenty-four baseline variables possibly influencing disease state and drug response were selected. In addition, 17 polymorphisms in 13 genes related to the MTX mechanism of action, purine and pyrimidine synthesis, were determined. Factors were compared between responders (defined as patients with a DAS <2.4 at 6 months) and nonresponders. In case of differences, a stepwise selection procedure identified the predictors for response. A clinical score was designed by simplifying regression coefficients of the independent variables. Cutoff levels were chosen based on the clinical score, and positive and negative response rates were calculated. An evaluation of the model was performed in a second group of patients.Results. The model for MTX efficacy consisted of sex, rheumatoid factor and smoking status, the DAS, and 4 polymorphisms in the AMPD1, ATIC, ITPA, and MTHFD1 genes. This prediction model was transformed into a scoring system ranging from 0 to 11.5. Scores of <3.5 had a true positive response rate of 95%. Scores of >6 had a true negative response rate of 86%. Sixty percent of the patients were categorized as either responders or nonresponders, whereas 32% of the patients were categorized using a nongenetic model. Evaluation of the model in 38 additional patients with RA supported the results.Conclusion. This study established a model for predicting the efficacy of MTX in patients with RA. This pharmacogenetic model may lead to better-tailored initial treatment decisions in patients with RA.

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“…The C452T polymorphism of GGH was determined by a PCR-RFLP reported by Chave et al with a minor modification. 14) Genomic DNA (100 ng) was amplified in 1ϫPCR buffer containing 200 mM concentrations of dNTP mixture (Applied Biosystems, Foster City, CA, U.S.A.), 0.5 mmol each of forward primer (5Ј-GTG CCT ATT TGG TTA TGA CA-3Ј) and reverse primer (5Ј-CTA CTT ACT AAT CCT GCC CA-3Ј), 0.5 units HotStar Taq DNA polymerase (Qiagen), and 1.5 mM MgCl 2 . Amplification was performed by i-Cycler thermal cycler (Bio-Rad, Hercules, CA, U.S.A.).…”

Section: Methodsmentioning

confidence: 99%

Genetic Polymorphism of C452T (T127I) in Human .GAMMA.-Glutamyl Hydrolase in a Japanese Population

Hayashi

Fujimaki

Inoue

et al. 2007

Biological & Pharmaceutical Bulletin

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We investigated the genotype distribution and allele frequency of C452T polymorphism of g g-glutamyl hydrolase (GGH) gene, which causes the decreased enzymatic activity affecting the efficacy of methotrexate (MTX), in a Japanese population. The polymerase chain reaction-restriction fragment length polymorphism assay was applied to determine the genotype of C452T polymorphism in 269 Japanese healthy individuals. The genotype distribution was as follows: C/C, 89.2% (n‫;)042؍‬ C/T, 10.4% (n‫;)82؍‬ T/T, 0.4% (n‫.)1؍‬ The frequency of C and T allele was 0.944 and 0.056, respectively. The obtained genotype distribution was well agreed with those expected by Hardy-Weinberg equilibrium. The genotype distribution and allele frequency in a Japanese population were found to be similar to those of African-Americans but significantly different from Caucasians. Although the frequency of variant T allele in a Japanese population is not so high as compared to Caucasians, determination of C452T polymorphism of GGH may be useful for monitoring of efficacy and side-effects of MTX for treatment of diseases such as rheumatoid arthritis or childhood acute leukemia. To our knowledge, this is the first report about the examination of C452T polymorphism of GGH in a Japanese population.

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Identification of single nucleotide polymorphisms in the human γ-glutamyl hydrolase gene and characterization of promoter polymorphisms

Cited by 76 publications

References 20 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

A clinical pharmacogenetic model to predict the efficacy of methotrexate monotherapy in recent‐onset rheumatoid arthritis

Genetic Polymorphism of C452T (T127I) in Human .GAMMA.-Glutamyl Hydrolase in a Japanese Population

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