Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:1.5.7.1 (methylenetetrahydrofolate reductase)
2,116 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Folate metabolism supports the synthesis of nucleotides as well as the transfer of methyl groups. Polymorphisms in folate-metabolizing enzymes have been shown to affect risk of colorectal neoplasia and other malignancies. Using data from a population-based incident case-control study (1,600 cases and 1,962 controls), we investigated associations between genetic variants in the reduced folate carrier (RFC), thymidylate synthase (TS), methionine synthase (MTR), and 5,10-methylenetetrahydrofolate reductase (MTHFR) and colon cancer risk. The TS enhancer region (TSER) variant was associated with a reduced risk among men [2rpt/2rpt versus 3rpt/3rpt wild-type; odds ratio (OR), 0.7; 95% confidence interval, 0.6-0.98] but not women. When combined genotypes for both TS polymorphisms (TSER and 3'-untranslated region 1494delTTAAAG) were evaluated, ORs for variant genotypes were generally below 1.0, with statistically significantly reduced risks among women. Neither MTR D919G nor RFC 80G>A polymorphisms were associated with altered colon cancer risk. Because folate metabolism is characterized by interrelated reactions, we evaluated gene-gene interactions. Genotypes resulting in reduced MTHFR activity in conjunction with low TS expression were associated with a reduced risk of colon cancer. When dietary intakes were taken into account, individuals with at least one variant TSER allele (3rpt/2rpt or 2rpt/2rpt) were at reduced risk in the presence of a low folate intake. This study supports findings from adenoma studies indicating that purine synthesis may be a relevant biological mechanism linking folate metabolism to colon cancer risk. A pathway-based approach to data analysis is needed to help discern the independent and combined effects of dietary intakes and genetic variability in folate metabolism.
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PMID:Polymorphisms in the reduced folate carrier, thymidylate synthase, or methionine synthase and risk of colon cancer. 1628 71

Genetic instability, including chromosomal imbalance, is important in the pathogenesis of lymphoproliferative disorders such as non-Hodgkin lymphoma (NHL). DNA synthesis and methylation, which are closely linked to folate metabolism and transport, may be affected by polymorphisms in genes involved in these pathways. Folate metabolism polymorphisms have been linked to acute lymphoblastic leukemia and colorectal cancer. To evaluate whether genetic variation in folate metabolism and transport may have a role in determining the risk of developing NHL, we analyzed several polymorphisms using DNA obtained as part of a large U.K. population-based case-control study of lymphoma. Polymorphisms studied include methylenetetrahydrofolate reductase (MTHFR) 677 C >T and 1298 A >C, methionine synthase (MTR) 2756 A>G, serine hydroxymethyltransferase (SHMT1) 1420 C >T, thymidylate synthase (TYMS) 1494del6 and 28-bp repeat, and reduced folate carrier (RFC) 80 G >A. Increased risks for NHL [odds ratio (OR), 1.48; 95% confidence intervals (CI), 1.12-1.97], and marginal zone lymphoma (OR, 3.38; 95% CI, 1.30-8.82) were associated with the TYMS 2R/3R variant. Marginal increased risks were also observed for diffuse large B cell lymphoma with the TYMS homozygous 6 bp deletion (OR, 1.61; 95% CI, 0.99-2.60) and for follicular lymphoma with RFC 80AA (OR, 1.44; 95% CI, 0.94-2.22) and TYMS 28-bp repeat 2R/3R (OR, 1.45; 95% CI, 0.96-2.2). We observed no association between NHL and haplotypes for MTHFR or TYMS. These findings are somewhat inconsistent with those of others, but may reflect differences in circulating folate levels between study populations. Thus, further investigations are warranted in larger series with dietary information to determine the roles that genetics and folic acid status play in the etiology of lymphoma.
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PMID:Risk of non-Hodgkin lymphoma associated with polymorphisms in folate-metabolizing genes. 1636 25

Patients with chronic kidney disease who are on dialysis or with a kidney transplant have higher total plasma homocysteine concentrations than individuals who are free from kidney disease. Several single-nucleotide polymorphisms of genes encoding enzymes that are involved in homocysteine metabolism have been studied in these patients. These polymorphisms are located in genes encoding of 5,10-methylenetetrahydrofolate reductase (MTHFR), methionine synthase reductase, methionine synthase, cystathionine beta-synthase, glutamate carboxy peptidase II, reduced folate carrier 1, and transcobalamin II. Among the single-nucleotide polymorphisms studied, only MTHFR 677C>T was associated consistently with total plasma homocysteine levels, but there currently is no evidence of any association between MTHFR 677C>T genotype and long-term outcomes.
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PMID:Genetic aspects of hyperhomocysteinemia in chronic kidney disease. 1641 18

The authors investigated whether high-dose methotrexate-induced toxicity differed according to the presence of methylenetetrahydrofolate reductase (MTHFR) or reduced folate carrier 1 (RFC1) genetic polymorphism. The authors studied 15 children with acute lymphoblastic leukemia or lymphoblastic lymphoma who were treated using protocols that included high-dose methotrexate (3.0 g/m), for an overall total of 43 courses. Methotrexate-induced toxicities and the plasma methotrexate concentrations were evaluated retrospectively. Hematologic toxicity was the most frequently observed toxicity, appearing in 87% of the patients. In a subset of patients (47%), elevation of liver transaminase levels showed a repeated tendency to develop. High plasma methotrexate concentrations at 48 hours after the methotrexate infusion were not significantly related to methotrexate-induced toxicities except for mucositis. A generalized estimating equation analysis revealed that vomiting during the high-dose methotrexate treatment was more pronounced in patients who had a larger number of G alleles at the RFC1 80G>A polymorphism. No significant differences in the development of other toxicities or in the plasma methotrexate concentrations were observed for the different MTHFR 677C>T or RFC1 80G>A polymorphisms. This study suggests but does not prove that the RFC1 80G>A polymorphism may contribute to interindividual variability in responses to high-dose methotrexate.
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PMID:Effects of methylenetetrahydrofolate reductase and reduced folate carrier 1 polymorphisms on high-dose methotrexate-induced toxicities in children with acute lymphoblastic leukemia or lymphoma. 1646 75

Maternal impairments in folate metabolism and elevated homocysteinemia are known risk factors for having a child with Down syndrome (DS) at a young age. The 80G>A polymorphism of the reduced folate carrier gene (RFC-1) has been recently demonstrated to affect plasma folate and homocysteine levels, alone or in combination with the 677C>T polymorphism in the methylenetetrahydrofolate reductase (MTHFR) gene. We performed the present study on 80 Italian mothers of DS individuals, aged less than 35 at conception, and 111 Italian control mothers, to study the role of the RFC-1 80G>A, MTHFR 677C>T, and MTHFR 1298A>C genotypes to the risk of a DS offspring at a young maternal age. When polymorphisms were considered alone, both allele and genotype frequencies did not significantly differ between DS mothers and control mothers. However, the combined MTHFR677TT/RFC-1 80GG genotype was borderline associated with an increased risk (OR 6 (CI 95%: 1.0-35.9), P = 0.05), and to be MTHF1298AA/RFC-1 80(GA or AA) was inversely associated with the risk (OR 0.36 (CI 95%: 0.14-0.96), P = 0.04). Present results seem to indicate that none of the RFC-1 80G>A, MTHFR 677C>T, and MTHFR 1298A>C polymorphisms is an independent risk factor for a DS offspring at a young maternal age; however, a role for the combined MTHFR/RFC-1 genotypes in the risk of DS pregnancies among young Italian women cannot be excluded.
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PMID:Folate gene polymorphisms and the risk of Down syndrome pregnancies in young Italian women. 1743 99

The aetiology of non-syndromic cleft lip with or without cleft palate (CL/P) is very complex. It has been shown that polymorphic variants of genes encoding key proteins of folate and methionine metabolism might be important maternal risk factors of having a child with this craniofacial anomaly. Therefore, in our study, mothers with CL/P children as well as control mothers were examined for prevalence of polymorphisms of genes that encode methylenetetrahydrofolate reductase (MTHFR), methionine synthase (MTR), 5,10-methylenetetrahydrofolate dehydrogenase, 5,10-methenyltetrahydrofolate cyclohydrolase and 10-formyltetrahydrofolate synthetase (MTHFD1) and reduced folate carrier 1 (RFC1). We observed that there were no statistical differences in allele and genotype frequencies of MTHFR c.677C>T, MTHFD1 c.1958G>A and RFC1 c.80G>A between mothers who had children with CL/P and control mothers. However, mothers with MTR c.2756AG or GG genotype displayed a 2.195-fold increased risk of having a child with CL/P (95% CI 1.189-4.050, p = 0.011). The mechanism by which polymorphic transition of MTR gene might increase the maternal risk of having CL/P progeny is unknown. Our observations are consistent with a significant role of the methyl cycle in the development of craniofacial structures in humans.
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PMID:Maternal MTR genotype contributes to the risk of non-syndromic cleft lip and palate in the Polish population. 1671 3

Autism is a behaviorally defined neurodevelopmental disorder usually diagnosed in early childhood that is characterized by impairment in reciprocal communication and speech, repetitive behaviors, and social withdrawal. Although both genetic and environmental factors are thought to be involved, none have been reproducibly identified. The metabolic phenotype of an individual reflects the influence of endogenous and exogenous factors on genotype. As such, it provides a window through which the interactive impact of genes and environment may be viewed and relevant susceptibility factors identified. Although abnormal methionine metabolism has been associated with other neurologic disorders, these pathways and related polymorphisms have not been evaluated in autistic children. Plasma levels of metabolites in methionine transmethylation and transsulfuration pathways were measured in 80 autistic and 73 control children. In addition, common polymorphic variants known to modulate these metabolic pathways were evaluated in 360 autistic children and 205 controls. The metabolic results indicated that plasma methionine and the ratio of S-adenosylmethionine (SAM) to S-adenosylhomocysteine (SAH), an indicator of methylation capacity, were significantly decreased in the autistic children relative to age-matched controls. In addition, plasma levels of cysteine, glutathione, and the ratio of reduced to oxidized glutathione, an indication of antioxidant capacity and redox homeostasis, were significantly decreased. Differences in allele frequency and/or significant gene-gene interactions were found for relevant genes encoding the reduced folate carrier (RFC 80G > A), transcobalamin II (TCN2 776G > C), catechol-O-methyltransferase (COMT 472G > A), methylenetetrahydrofolate reductase (MTHFR 677C > T and 1298A > C), and glutathione-S-transferase (GST M1). We propose that an increased vulnerability to oxidative stress (endogenous or environmental) may contribute to the development and clinical manifestations of autism.
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PMID:Metabolic endophenotype and related genotypes are associated with oxidative stress in children with autism. 1691 39

Methotrexate is administered in high doses to treat childhood acute lymphoblastic leukemia and malignant lymphoma. Hepatotoxicity and bone marrow suppression often limit its use, however. The objective of this study was to determine the genetic polymorphisms associated with the hepatotoxicity and elimination of methotrexate. Genetic polymorphisms of glutathione S-transferase (GST) genes including GSTT1 positive/null, GSTM1 positive/null, and GSTP1 A313G, and genes for reduced folate carrier 1 G80A (RFC1 G80A), methylenetetrahydrofolate reductase C677T (MTHFR C677T), and breast cancer resistant protein C421A (BCRP C421A) were determined for 26 patients by the polymerase chain reaction (PCR) method or by direct sequencing. A high frequency of hepatotoxicity (P = 0.035) was observed for patients with GSTM1 positive and RFC1 AA(80), and serum concentrations of methotrexate 48 h after the start of infusion were higher for patients with the TT(677) genotype of MTHFR (P = 0.028). In conclusion, GSTM1 positive/null and RFC1 G80A polymorphisms could be predictors for hepatotoxicity, and the MTHFR C677T polymorphism is associated with elimination of methotrexate.
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PMID:Genetic polymorphisms associated with adverse events and elimination of methotrexate in childhood acute lymphoblastic leukemia and malignant lymphoma. 1718 May 79

Multiple studies have reported an association between disturbances of folate metabolism and increased risk of gastric cancer, including low intake of folate, low levels of folate in blood or genetic factors affecting folate metabolism. Among the genetic factors, in particular a common polymorphism in the gene encoding for 5,10-methylenetetrahydrofolate reductase (MTHFR C677T) has been linked to gastric cancer. Other polymorphisms in folate-metabolising genes have been less frequently investigated. Therefore, we analyzed this polymorphism, the glutamate carboxypeptidase (GCP) II C1561T and the reduced folate carrier (RFC) G80A in a case-control study involving 106 patients with histologically confirmed and characterized gastric cancer with adjustment for other established risk factors for gastric cancer in comparison to 106 age- and sex-matched controls. Neither the MTHFR nor the GCP gene polymorphisms showed an association to cancer diagnosis, to tumor stage, grade of differentiation or Lauren type. However, non-cardia cancers were more likely to exhibit the 80GA and 80AA RFC genotypes, compared to cancers of the gastric cardia (adjusted OR 0.28; 95% CI=0.11-0.71). Thus, gene polymorphisms of the RFC gene might contribute to an increased risk of developing distal gastric cancer.
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PMID:Gene polymorphisms of folate metabolizing enzymes and the risk of gastric cancer. 1720 63

Several polymorphisms of genes involved in one-carbon metabolism have been identified. The reported metabolic phenotypes are often based on small studies providing inconsistent results. This large-scale study of 10,601 population-based samples was carried out to investigate the association between a panel of biochemical parameters and genetics variants related to one-carbon metabolism. Concentrations of total homocysteine (tHcy), folate, vitamin B(12) (cobalamin), methylmalonic acid (MMA), vitamin B(2) (riboflavin), vitamin B(6) (PLP), choline, betaine, dimethylglycine (DMG), cystathionine, cysteine, methionine, and creatinine were determined in serum/plasma. All subjects were genotyped for 13 common polymorphisms: methylenetetrahydrofolate reductase (MTHFR) c.665C>T (known as 677C>T; p.Ala222Val) and c.1286A>C (known as 1298A>C; p.Glu429Ala); methionine synthase (MTR) c.2756A>G (p.Asp919Gly); methionine synthase reductase (MTRR) c.66A>G (p.Ile22Met); methylenetetrahydrofolate dehydrogenase (MTHFD1) c.1958G>A (p.Arg653Gln); betaine homocysteine methyltransferase (BHMT) c.716G>A (known as 742G>A; p.Arg239Gln); cystathionine beta-synthase (CBS) c.844_845ins68 and c.699C>T (p.Tyr233Tyr); transcobalamin-II (TCN2) c.67A>G (p.Ile23Val) and c.776C>G (p.Pro259Arg); reduced folate carrier-1 (SLC19A1) c.80G>A (p.Arg27His); and paraoxonase-1 (PON1) c.163T>A (p.Leu55Met) and c.575A>G (p.Gln192Arg). The metabolic profile in terms of the measured vitamins and metabolites were investigated for these 13 polymorphisms. We confirmed the strong associations of MTHFR c.665C>T with tHcy and folate, but also observed significant (P<0.01) changes in metabolite concentrations according to other gene polymorphisms. These include MTHFR c.1286A>C (associations with tHcy, folate and betaine), MTR c.2756A>G (tHcy), BHMT c.716G>A (DMG), CBS c.844_845ins68 (tHcy, betaine), CBS c.699C>T (tHcy, betaine, cystathionine) and TCN2 c.776C>G (MMA). No associations were observed for the other polymorphisms investigated.
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PMID:Large-scale population-based metabolic phenotyping of thirteen genetic polymorphisms related to one-carbon metabolism. 1743 11


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