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)

An increased occurrence of colorectal cancer and its adenoma precursor is observed among individuals with low intakes or circulating levels of folate, especially if alcohol intake is high, although results have not been statistically significant in all studies. We examined folate and alcohol intake and genetic polymorphisms in methylenetetrahydrofolate reductase [MTHFR 667-->T (ala-->val) and MTHFR 1298A-->C (gln-->ala)] (associated with reduced MTHFR activity) and in alcohol dehydrogenase 3 [ADH3 (2-2) associated with decreased alcohol catabolism] in relation to risk of colorectal adenoma in the Health Professionals Follow-Up Study. Among 379 cases and 726 controls, MTHFR genotypes were not appreciably related to risk of adenoma, but a suggestive interaction (P = 0.09) was observed between MTHFR 677C-->T and alcohol intake; men with TT homozygotes who consumed 30+ g/day of alcohol had an odds ratio (OR) of 3.52 [95% confidence interval (CI), 1.41-8.78] relative to drinkers of < or =5 g/day with the CC/CT genotypes. ADH3 genotype alone was not appreciably related to risk, but its influence was modified by alcohol intake. Compared with fast alcohol catabolizers [ADH3(1-1)] with low intakes of alcohol (< or =5 g/day), high consumers of alcohol (30+ g/day) had a marked increase in risk if they had the genotype associated with slow catabolism [ADH3(2-2); OR, 2.94; 95% CI, 1.24-6.92] or intermediate catabolism [ADH3(1-2)] of alcohol (OR, 1.83; 95% CI, 1.03-3.26) but not if they were fast catabolizers [ADH3(1-1); OR = 1.27; 95% CI = 0.63-2.53). In addition, an increased risk of colorectal adenoma (OR, 17.1; 95% CI, 2.1-137) was observed for those with the ADH3(2-2) genotype and high alcohol-low folate intake compared with those with low alcohol-high folate intake and the ADH3(1-1) genotype (P for interaction = 0.006). Our results indicate that high intake of alcohol is associated with an increased risk of colorectal adenoma, particularly among MTHFR 677TT and ADH3(2-2) homozygotes. The findings that alcohol interacts with a folate-related gene (MTHFR) and that the interaction between alcohol and ADH3 is stronger among those with low folate intake support the hypothesis that the carcinogenic influence of alcohol in the large bowel is mediated through folate status.
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PMID:Methylenetetrahydrofolate reductase, alcohol dehydrogenase, diet, and risk of colorectal adenomas. 1457 31

So far, evidence for the relation between folate intake and colorectal cancer has been insufficient to lead to specific public health interventions. In principle, data on the relation between genetic variation in folate metabolism and colorectal neoplasia could be used to corroborate the data on the relation between folate intake or status and the disease, strengthening the evidence base for primary prevention. Issues in considering the relation between a health outcome and genetic variation in metabolism of nutrients or other food components include knowledge of gene function, linkage disequilibrium, population stratification, study size and quality, and gene-environment interaction. Overall homozygosity for MTHFR variant genotypes is associated with a reduced risk of colorectal cancer, the opposite of what might have been expected a priori. This has led investigators to place greater emphasis on the functions of folate and methylenetetrahydrofolate reductase in DNA synthesis. Folate and related nutrients may be important after adenoma formation. A challenge for the future is to characterize the effects of multiple genes influencing folate metabolism. Limited data for colorectal cancer suggest that the effect of a low folate diet overrides the effect of genotype, but two studies of adenomas suggested the opposite. Another potential role of information on genetic variation in folate metabolism is in the management of colorectal cancer but most studies have been small, have included selected patient groups, and have made limited adjustment for potentially important factors.
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PMID:Colon cancer and genetic variation in folate metabolism: the clinical bottom line. 1460 11

One-carbon metabolism is under the influence of folate, vitamin B12 and genetic polymorphisms of methylenetetrahydrofolate reductase (MTHFR 677 C --> T and 1298 A --> C), of methionine synthase (MTR 2756 C --> G), methionine synthase reductase (MTRR 66 A --> G) and transcobalamin (TCN 776 C --> G). The pathogenesis of neural tube defect (NTD) may be related to this metabolism. The influence of the MTHFR 677 C --> T polymorphism reported in The Netherlands and Ireland can be questioned in southern Italy, France and Great Britain. MTRR, combined with a low level of vitamin B12, increases the risk of NTD and of having a child with NTD in Canada, while TCN 776 GG and MTRR 66 GG mutated genotypes associated with the MTHFR 677 CC wild-type are predictors of NTD cases in Sicily. Down syndrome (DS) is due to a failure of normal chromosomal segregation during meiosis, possibly related to one-carbon metabolism. MTHFR 677 C --> T and MTRR 66 A --> G polymorphisms are associated with a greater risk of having a child with DS in North America, Ireland and The Netherlands. In contrast, MTHFR 677 C --> T has no influence on DS risk in France and Sicily, while homocysteine and MTR 2756 AG/GG genotypes are predictors of DS risk in Sicily. In conclusion, NTD and DS are influenced by the same genetic determinants of one-carbon metabolism. The distinct data produced in different geographical areas may be explained by differences in the nutritional environment and genetic characteristics of the populations.
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PMID:Genetic determinants of folate and vitamin B12 metabolism: a common pathway in neural tube defect and Down syndrome? 1465 28

Epidemiologic and mechanistic evidence suggests that folate is involved in colorectal neoplasia. Some polymorphic genes involved in folate metabolism--methylenetetrahydrofolate reductase (MTHFR C677T and A1298C), methionine synthase (MTR A2756G), methionine synthase reductase (MTRR A66G), cystathionine beta-synthase (CBS exon 8, 68-base-pair insertion), and thymidylate synthase (TS enhancer region and 3' untranslated region)--have been investigated in colorectal neoplasia. For MTHFR C677T and A1298C, the variant allele is associated with reduced enzyme activity in vitro. For the other polymorphisms, functional data are limited and/or inconsistent. Genotype frequencies for all of the polymorphisms show marked ethnic and geographic variation. In most studies, MTHFR 677TT (10 studies, >4,000 cases) and 1298CC (four studies, >1,500 cases) are associated with moderately reduced colorectal cancer risk. In four of five genotype-diet interaction studies, 677TT subjects who had higher folate levels (or a "high-methyl diet") had the lowest cancer risk. In two studies, 677TT homozygote subjects with the highest alcohol intake had the highest cancer risk. Findings from six studies of MTHFR C677T and adenomatous polyps are inconsistent. There have been only one or two studies of the other polymorphisms; replication is needed. Overall, the roles of folate-pathway genes, folate, and related dietary factors in colorectal neoplasia are complex. Research priorities are suggested.
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PMID:Polymorphisms in genes involved in folate metabolism and colorectal neoplasia: a HuGE review. 1497 39

Homocysteine metabolism is influenced by genetic polymorphisms of the methylenetetrahydrofolate reductase (MTHFR 677 C-->T and 1298 A-->C) and transcobalamin genes (TCN1 776 C-->G ). We evaluated the association of homocysteine with Alzheimer's disease (AD) and the influence of related polymorphisms and APOE, in 180 cases and 181 controls from southern Italy. Homocysteine (upper tercile) was associated with AD risk, with an odds ratio of 2.8 (95% confidence interval (CI) 1.54-5.22, p=0.0008), which was increased 2.2- and 2.0-fold by MTHFR 677T (odds ratio 6.28, 95% CI 2.88-16.20, p < 0.0001) and APOE epsilon4 (odds ratio: 5.60, 95% CI 1.12-28.05, p=0.0361), respectively. In conclusion, association of homocysteine with AD was aggravated by MTHFR 677T and APOE epsilon4 alleles.
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PMID:Homocysteine and methylenetetrahydrofolate reductase polymorphism in Alzheimer's disease. 1507 31

Plasma total homocysteine (tHcy) concentration, an independent risk factor of atherosclerosis, has numerous genetic and environmental determinants. While the thermolabile polymorphism in MTHFR encoding methylenetetrahydrofolate reductase is the best-studied genetic factor associated with variation in plasma tHCy, other candidate genes are being evaluated. Recently, we discovered that cystathioninuria was caused by mutations in the CTH gene encoding cystathionine gamma-lyase, an enzyme that converts cystathionine to cysteine in the trans-sulfuration pathway. We also identified a common single nucleotide polymorphism (SNP), namely c.1364G>T (S403I) in exon 12 of CTH. In the current analysis, we studied the association of genotypes of this SNP with plasma tHcy concentrations in 496 Caucasian subjects. CTH 1364T/T homozygotes had significantly higher mean plasma tHcy concentration than subjects with other genotypes, and the effect sizes of CTH and MTHFR genotypes were similar. The findings suggest that common variation in CTH may be a determinant of plasma tHcy concentrations.
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PMID:Single nucleotide polymorphism in CTH associated with variation in plasma homocysteine concentration. 1515 7

Folate and methionine metabolism is involved in DNA synthesis and methylation processes. Polymorphisms in the genes of folate metabolism enzymes have been associated with some forms of cancer. In a case-control study, we evaluated whether four common polymorphisms in methylenetetrahydrofolate reductase (MTHFR C677T and A1298C), methionine synthase (MS A2756G), and methionine synthase reductase (MTRR A66G) genes may have a role in altering susceptibility to adult acute lymphoblastic leukemia (ALL) and non-Hodgkin's lymphoma (NHL). We analyzed DNA of 120 adult ALL, 200 NHL, and 257 healthy control subjects. Individual carrying the MTHFR 677TT genotype showed a 3.6-fold decreased ALL risk [odds ratio (OR) 0.28, 95% confidence interval (95% CI) 0.12-0.72] than wild-types. Similarly, MS 2756GG individuals showed a 5.0-fold decreased ALL risk (OR 0.20, 95% CI 0.02-1.45) than wild-types. In combined results, subjects with the MTHFR 677CT/TT and MS 2756AG/GG genotypes revealed a 3.6-fold ALL risk reduction (OR 0.28, 95% CI 0.14-0.58) and those with the MTHFR 677TT and MTRR 66AG genotypes revealed a 4.2-fold ALL risk reduction (OR 0.24, 95% CI 0.06-0.81). Finally, those with the MS 2756AG/GG and MTRR 66AG/GG genotypes revealed a 2.2-fold ALL risk reduction (OR 0.45, 95% CI 0.10-0.85). Single analysis for NHL did not show any significant difference for all the polymorphisms investigated, but in the low-grade NHL subgroup, we found a 2.0-fold risk reduction for the MTRR 66GG homozygous genotype (OR 0.50, 95% CI 0.25-0.99), which was higher (OR 0.37, 95% CI 0.14-0.85) when analyzed in combination with MS 2756AA genotype. These data are in accordance with the hypothesis that polymorphisms in the genes for folate and methionine metabolism might play a greater role in the occurrence of ALL than NHL by influencing DNA synthesis and/or DNA methylation.
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PMID:Common gene polymorphisms in the metabolic folate and methylation pathway and the risk of acute lymphoblastic leukemia and non-Hodgkin's lymphoma in adults. 1515 11

Folate metabolism plays an essential role in DNA synthesis and methylation processes. Deviations in the flux of folate due to genetic variation could result in selective growth and genomic instability and affect susceptibility to various cancers including lymphoma. To test this hypothesis, genetic polymorphisms in the folate metabolic pathway were investigated using DNA from a population-based case-control study of non-Hodgkin lymphoma (NHL) conducted in the San Francisco Bay Area between 1988 and 1995. The polymorphisms examined and haplotypes generated included thymidylate synthase (TYMS 28-bp triple repeat [3R]-->double repeat [2R], 1494del6, IVS6 -68C>T, 1122A>G, and 1053C>T); 5,10-methylenetetrahydrofolate reductase (MTHFR 677C>T and 1298A>C); serine hydroxymethyltransferase (SHMT1 C1420T); reduced folate carrier (RFC G80A); and methionine synthase (MTR A2756G), making the present study the largest and most comprehensive to date to evaluate associations between genetic polymorphisms in folatemetabolizing genes and NHL risk. The TYMS 6 base pair (bp)(-)6bp- (homozygous for 6bp deletion), IVS6 -68C>T, and 1053C>T genotypes (all in complete linkage disequilibrium) were all inversely associated with NHL (TYMS; odds ratio [OR] = 0.57; 0.34-0.94), particularly with diffuse large cell lymphoma (DLCL; OR = 0.29; 0.10-0.82). Further, the MTR 2756AG/GG and the MTHFR 677TT genotypes were associated with increased risk for NHL (OR = 1.3; 0.99-1.7) and follicular lymphoma (FL; OR = 1.8; 0.98-3.1), respectively. We did not observe any significant differences in genotype frequencies of the SHMT1 and RFC polymorphisms between the cases and controls. The associations of DLCL and FL with TYMS 1494del6 and MTHFR 677TT genotypes, respectively, suggest that folate metabolism may play an important role in the pathogenesis of specific subtypes of NHL.
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PMID:Polymorphisms and haplotypes in folate-metabolizing genes and risk of non-Hodgkin lymphoma. 1563 15

MTHFR (methylenetetrahydrofolate reductase) catalyses the synthesis of 5-methyltetrahydrofolate, the folate derivative utilized in homocysteine remethylation to methionine. A severe deficiency of MTHFR results in hyperhomocysteinaemia and homocystinuria. Betaine supplementation has proven effective in ameliorating the biochemical abnormalities and the clinical course in patients with this deficiency. Mice with a complete knockout of MTHFR serve as a good animal model for homocystinuria; early postnatal death of these mice is common, as with some neonates with low residual MTHFR activity. We attempted to rescue Mthfr-/- mice from postnatal death by betaine supplementation to their mothers throughout pregnancy and lactation. Betaine decreased the mortality of Mthfr-/- mice from 83% to 26% and significantly improved somatic development from postnatal day 1, compared with Mthfr-/- mice from unsupplemented dams. Biochemical evaluations demonstrated higher availability of betaine in suckling pups, decreased accumulation of homocysteine, and decreased flux through the trans-sulphuration pathway in liver and brain of Mthfr-/- pups from betaine-supplemented dams. We observed disturbances in proliferation and differentiation in the cerebellum and hippocampus in the knockout mice; these changes were ameliorated by betaine supplementation. The dramatic effects of betaine on survival and growth, and the partial reversibility of the biochemical and developmental anomalies in the brains of MTHFR-deficient mice, emphasize an important role for choline and betaine depletion in the pathogenesis of homocystinuria due to MTHFR deficiency.
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PMID:Betaine rescue of an animal model with methylenetetrahydrofolate reductase deficiency. 1521 52

Recently, it has been proposed that abnormalities in coagulation and fibrinolysis contribute to the development of preeclampsia by increasing the thrombotic tendency. This hypothesis was tested in women who have had preeclampsia (cases) compared with matched controls. Polymorphisms in the thrombophilia genes [plasminogen activator inhibitor type 1 [PAI-1 -675(4G/5G)], thrombin activatable fibrinolysis inhibitor (TAFI -438G/A and 1040C/T), methylenetetrahydrofolate reductase (MTHFR 677C/T), factor V (FV Leiden R/Q506), prothrombin (FII 20210G/A) and factor XIIIA (FXIIIA V/L34)] were determined in 157 women with preeclampsia and 157 women with uncomplicated pregnancy. The associated risk of preeclampsia was analyzed using logistic regression methods. The frequency distributions of the genotypes of these six polymorphisms in thrombophilia genes were similar in the case and control groups. We found no differences in the prevalence of genetic risk factors of thrombosis in women with preeclampsia compared with controls, which makes it unlikely that these polymorphisms are risk factors for preeclampsia.
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PMID:Preeclampsia and its interaction with common variants in thrombophilia genes. 1533 35


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