The 1298A→C polymorphism in methylenetetrahydrofolate reductase (MTHFR): in vitro expression and association with homocysteine

Weisberg, Ilan

doi:10.1016/s0021-9150(00)00671-7

Cited by 335 publications

(265 citation statements)

References 19 publications

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“…Here, the results indicate that the polymorphism MTHFR 677 TT is associated with a decrease in Hcy concentration. This was an unexpected finding as previous studies have shown that the MTHFR 677 T allele is associated with reduced MTHFR enzyme activity [26] and increased Hcy concentration [5,20,[23][24][25]. Licastro et al [5] observed elevated Hcy concentrations in elderly DS individuals with the MTHFR 677 TT genotype; however, in other studies that used both children and adults with DS, no association between the MTHFR C677T polymorphism and Hcy concentration was seen [19,27].…”

Section: Discussionmentioning

confidence: 90%

Genetic polymorphisms modulate the folate metabolism of Brazilian individuals with Down syndrome

et al. 2012

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Individuals with Down syndrome (DS) carry three copies of the Cystathionine b-synthase (CbS) gene. The increase in the dosage of this gene results in an altered profile of metabolites involved in the folate pathway, including reduced homocysteine (Hcy), methionine, S-adenosylhomocysteine (SAH) and S-adenosylmethionine (SAM). Furthermore, previous studies in individuals with DS have shown that genetic variants in genes involved in the folate pathway influence the concentrations of this metabolism's products. The purpose of this study is to investigate whether polymorphisms in genes involved in folate metabolism affect the plasma concentrations of Hcy and methylmalonic acid (MMA) along with the concentration of serum folate in individuals with DS. Twelve genetic polymorphisms were investigated in 90 individuals with DS (median age 1.29 years, range 0.07-30.35 years; 49 male and 41 female). Genotyping for the polymorphisms was performed either by polymerase chain reaction (PCR) based techniques or by direct sequencing. Plasma concentrations of Hcy and MMA were measured by liquid chromatography-tandem mass spectrometry as previously described, and serum folate was quantified using a competitive immunoassay. Our results indicate that the MTHFR C677T, MTR A2756G, TC2 C776G and BHMT G742A polymorphisms along with MMA concentration are predictors of Hcy concentration. They also show that age and Hcy concentration are predictors of MMA concentration. These findings could help to understand how genetic variation impacts folate metabolism and what metabolic consequences these variants have in individuals with trisomy 21.

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Section: Discussionmentioning

confidence: 90%

Genetic polymorphisms modulate the folate metabolism of Brazilian individuals with Down syndrome

et al. 2012

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“…This genetic mutation is present in 1 to 2% of the general population but the prevalence is 4 to 20% in selected high-risk groups such as patients with thrombosis. 20 Methylene-tetrahydrofolate reductase (MTHFR) 677C>T (MTHFR667) and MTHFR1298A>C (MTHFR1298) mutations cause altered MTHFR activity leading to increased plasma levels of homocysteine, 16,[20][21][22] especially in folate-deficient patients. Hyperhomocystenemia has been associated with an increased risk of thrombosis.…”

Section: Introductionmentioning

confidence: 99%

“…In addition, the combined heterozygosity of MTHFR 677 and 1298 increases homocysteine levels significantly and it has been suggested that this is a possible important risk factor. 21,22 Ultrasound scan has been used successfully to identify large vessel thrombus. 5,26 It is a safe, readily available test that can be done at the bedside.…”

Section: Introductionmentioning

confidence: 99%

Genetic prothrombotic mutations are common in neonates but are not associated with umbilical catheter-associated thrombosis

et al. 2007

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Objective: To evaluate the prevalence of hereditary prothrombotic mutations, and their effect on the incidence and severity of umbilical arterial or venous catheter (UAC or UVC)-associated thrombosis.Study Design: All neonates with a UAC or UVC were studied prospectively for the presence, severity and timing of thrombosis with duplex Doppler ultrasound scan. Genetic testing for factor V Leiden (FVL), prothrombin mutation (PTm) and methylene-tetrahydrofolate reductase (MTHFR) mutations was performed using PCR and restriction fragment length polymorphism assays.Result: Umbilical catheter (UC)-associated thrombosis developed in 16/53 (31%) neonates; 23% of UACs and 22% of UVCs were associated with thrombosis. The prevalence of a significant prothrombotic mutation was present in 10/51 (20%) of infants: FVL (8%), MTHFR667 homozygosity (10%), MTHFR1298 homozygosity (2%) and PTm (0%). There was no increase in the risk of UC-associated thrombus in patients carrying these prothrombotic mutations; our study had the power to detect a 2.5-fold increased risk of thrombosis for any of these significant mutations. In addition, MTHFR667 heterozygosity was found in 41% of infants and MTHFR1298 heterozygosity in 52% and also were not associated with increased risk of UC-associated thrombus. The risk of MTHFR double heterozygosity (db het) was 14%, the risk of a significant or db het was 17/51 (33%) and the risk of any mutation was 90%.Conclusion: Prothrombotic genetic mutations are common in our Neonatal Intensive Care Unit population but do not appear to increase the risk of UC-associated thrombosis.

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“…4,5 Reduced enzymatic activity has been observed in TT677 or CC1298 homozygotes, and to a lesser extent in heterozygous individuals. 4,6,7 The role of MTHFR variants in a number of disorders, involving disturbances in folate metabolism, such as neural tube defects (NTDs), 8 vascular disease 9,10 and cancer susceptibility, is well documented. 11,12 Recently, the potential role of these polymorphisms in response to MTX treatment has been addressed in several studies.…”

Section: Introductionmentioning

confidence: 99%

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

153

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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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The 1298A→C polymorphism in methylenetetrahydrofolate reductase (MTHFR): in vitro expression and association with homocysteine

Cited by 335 publications

References 19 publications

Genetic polymorphisms modulate the folate metabolism of Brazilian individuals with Down syndrome

Genetic polymorphisms modulate the folate metabolism of Brazilian individuals with Down syndrome

Genetic prothrombotic mutations are common in neonates but are not associated with umbilical catheter-associated thrombosis

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

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