Polymorphism G80A in the reduced folate carrier gene and its relationship to methotrexate plasma levels and outcome of childhood acute lymphoblastic leukemia

Laverdière, Caroline; Chiasson, Sonia; Costea, Irina; Moghrabi, Albert; Krajinović, Maja

doi:10.1182/blood.v100.10.3832

Cited by 194 publications

(130 citation statements)

References 14 publications

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“…To date, most studies have shown that the MTHFR C677T genotype is related to biomarkers, such as serum folate, tHcy concentration, and folate intake. Other polymorphisms in the folate pathway have been found to be associated with a variety of complex traits and disorders including MTHFR A1298C, MTRR A66G, MTR A2756G, MTHFD1 G1958A, FOLH1 T484C, SLC19A1 A80G, and transcobalamin II ( TCN2 ) C776G, the transport protein of vitamin B12 (Weisberg et al 1998; Gaughan et al 2001; Laverdiere et al 2002; Kluijtmans et al 2003; Dervieux et al 2004; Martinelli et al 2006; Moskau et al 2007; Silva et al 2011; Pangilinan et al 2012; Xie et al 2012). Table 1 summarizes the distribution of serum tHcy, folate, vitamin B6, and vitamin B12 according to polymorphisms related to folate and tHcy metabolism (Hiraoka et al 2004; Hiraoka et al 2009).…”

Section: Genetic Polymorphisms Related To Folate and Thcy Metabolism mentioning

confidence: 99%

Genetic polymorphisms and folate status

Hiraoka

Kagawa

2017

Congenital Anomalies

134

102

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Moderate hyperhomocysteinemia‐induced low folate status is an independent risk factor for cardiovascular disease, dementia, and depression. Folate is an essential cofactor in the one‐carbon metabolism pathway and is necessary in amino acid metabolism, purine and thymidylate synthesis, and DNA methylation. In the folate cycle and homocysteine metabolism, folate, vitamin B12, vitamin B6, and vitamin B2 are important cofactors. Many enzymes are involved in folate transport and uptake, the folate pathway, and homocysteine (Hcy) metabolism, and various polymorphisms have been documented in these enzymes. Serum folate and total Hcy (tHcy) levels are influenced by folate intake and genetic polymorphisms in 5,10‐methylenetertahydrofolate reductase (MTHFR) such as C677T. The prevalence of the MTHFR 677TT genotype varies across ethnic groups and regions, with a frequency of approximately 15% in Japanese populations. Individuals with the TT genotype have significantly higher tHcy levels and lower folate levels in serum than those with the CT and TT genotypes. However, administration of folic acid has been shown to eliminate these differences. Moreover, data have suggested that interventions based on genotype may be effective for motivating individuals to change their lifestyle and improve their nutrition status. Accordingly, in this review, we discuss the effects of MTHFR C677T polymorphisms on serum tHcy and folate levels with folic acid intervention and evaluate approaches for overcoming folic acid deficiency and related symptoms.

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Section: Genetic Polymorphisms Related To Folate and Thcy Metabolism mentioning

confidence: 99%

Genetic polymorphisms and folate status

Hiraoka

Kagawa

2017

Congenital Anomalies

134

102

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“…24 The details of the MTX administration are given elsewhere. 41 Information concerning the reduction and increase of MTX dose carried out according to the protocols was available for 185 patients. Patient samples were obtained at diagnosis after informed consent.…”

Section: Study Populationmentioning

confidence: 99%

“…The distribution of prognostic factors at diagnosis (sex, age, white blood cell (WBC) count, ALL immunophenotype, treatment protocol, risk group and DNA index) among individuals with and without event was as described previously. 41 For analysis, patients were categorized according to relapse risk prediction (boys or girls; age below 1 year, 1-10 and above 10; WBC below or above of 50 Â 10 9 ; B-or Tcell type; standard, high or very high risk and DNA index above or below 1.16, corresponding to 50 chromosomes). 41 Children who relapsed or had a fatal outcome due to the disease were defined to have had an event.…”

Section: Study Populationmentioning

confidence: 99%

“…The HR (with a 95% CI) of the MTHFR and MTHFD1 variants was estimated by Cox's regression analysis, with and without the enclosure of prognostic factors (ie sex, age, WBC count, ALL cell type, treatment protocol, risk group and DNA index) or other genetic variants (TS triple repeat, RFC1 A 80 and CCND1 A870) previously shown to influence the risk of relapse. 24,41,43 In EFS analysis, survival time corresponded to the time between diagnoses and event (n ¼ 35), whereas for the censored cases it corresponded to time between diagnosis and the end of follow-up (5 years post-treatment) or February 2002 (for patients receiving therapy or those who have entered the follow-up period). In the event group, the survival time ranged from 1 to 84 months with a median of 19 months, and in the nonevent group, it ranged from 12 to 84 months with a median of 60 months.…”

Section: Study Populationmentioning

confidence: 99%

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

Krajinović

Lemieux-Blanchard²,

Chiasson³

et al. 2003

Pharmacogenomics J

152

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The central role of 5,10-methylenetetrahydrofolate reductase (MTHFR) and methylenetetrahydrofolate dehydrogenase (MTHFD1) in folate metabolism renders polymorphisms in genes encoding these enzymes potential modulators of therapeutic response to antifolate chemotherapeutics. The analysis of 201 children treated with methotrexate for childhood acute lymphoblastic leukemia (ALL) showed that patients with either the MTHFR T677A1298 haplotype or MTHFD1 A1958 variant had a lower probability of event-free survival (EFS) in univariate analysis (hazard ratio (HR) ¼ 2.2, 95% confidence interval (CI), 1.0-4.7 and 2.8, 95% CI, 1.1-7.3, respectively). Multivariate analysis supported only the role of the MTHFR variant (HR ¼ 2.2, 95% CI, 0.9-5.6). However, the association of both genes with ALL outcome appears to be more obvious in the presence of another event-predisposing variant belonging to the same path of drug action. The combined effect of a thymidylate synthase (TS) triple repeat associated with increased TS levels, with either the MTHFR T677A1298 haplotype or MTHFD1 A1958 allele, resulted in a highly significant reduction of EFS (multivariate HR ¼ 9.0, 95% CI, 1.9-42.8 and 8.9, 95% CI, 1.8-44.6, respectively). These results reveal the role of gene-gene interactions within a folate pathway, and how they can correlate with relapse probabilities in ALL patients.

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“…[6][7][8] In the present study, we examined the association between RFC-1 G80A polymorphism and treatment outcome in patients with RA administered MTX.…”

Section: Introductionmentioning

confidence: 99%

Reduced folate carrier-1 80G>A polymorphism affects methotrexate treatment outcome in rheumatoid arthritis

et al. 2007

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The folate antagonist methotrexate (MTX) is a drug currently used in the treatment of rheumatoid arthritis (RA). MTX enters the cells through the reduced folate carrier (RFC-1) and is activated to polyglutamates. Previous studies have shown that RFC-1 expression may influence the efficacy of therapy with MTX. The studies suggest that G80A polymorphism in RFC-1 is associated with altered folate/antifolate levels and the subjects carrying homozygous mutant 80AA genotype tend to have higher plasma folate and MTX concentrations and higher erythrocyte polyglutamate levels compared with those with the wild type or heterozygous genotype. It is possible that this polymorphism might influence MTX treatment outcome in patients with RA. In the present study, we examined the association between RFC-1 G80A polymorphism and treatment outcome in patients with RA administered MTX. The study was carried out on 174 patients diagnosed with RA treated with MTX (7.5-15.0 mg weekly) plus low doses of methylprednisone. The RFC-1 80G4A polymorphism (resulting in a histidine-to-arginine substitution at codon 27 of RFC-1) was detected using a polymerase chain reactionrestriction fragment length polymorphism method. The probability of remission of RA symptoms was 3.32-fold higher in carriers of 80AA genotype as compared with patients with 80GG genotype (P ¼ 0.021, OR ¼ 3.32,). The frequency of A allele among MTX responders was 62.1, compared to 47.8% in a group of poor MTX responders (P ¼ 0.013, OR ¼ 1.78, 95% CI: 1.13-2.81). Moreover, the increase of aminotransferase activity was noted more frequently in carriers of 80AA genotype. The present data suggest that evaluation of RFC-1 gene 80G4A polymorphism may be a useful tool to optimize MTX therapy in patients with RA.

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Polymorphism G80A in the reduced folate carrier gene and its relationship to methotrexate plasma levels and outcome of childhood acute lymphoblastic leukemia

Cited by 194 publications

References 14 publications

Genetic polymorphisms and folate status

Genetic polymorphisms and folate status

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

Reduced folate carrier-1 80G>A polymorphism affects methotrexate treatment outcome in rheumatoid arthritis

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