scholarly journals B-vitamins, homocysteine metabolism and CVD

2004 ◽  
Vol 63 (4) ◽  
pp. 597-603 ◽  
Author(s):  
J. J. Strain ◽  
L. Dowey ◽  
M. Ward ◽  
K. Pentieva ◽  
H. McNulty
Keyword(s):  
Methylenetetrahydrofolate Reductase ◽  
Independent Predictor ◽  
Systemic Disease ◽  
Plasma Concentrations ◽  
Nutrient Status ◽  
Mthfr Gene ◽  
Plasma Homocysteine ◽  
B Vitamins ◽  
Vitamin B ◽  
Pathophysiological Mechanism

The present review focuses on the B-vitamins, i.e. folate, vitamin B12, vitamin B6and riboflavin, that are involved in homocysteine metabolism. Homocysteine is a S-containing amino acid and its plasma concentrations can be raised by various constitutive, genetic and lifestyle factors, by inadequate nutrient status and as a result of systemic disease and various drugs. Hyperhomocysteinaemia is a modest independent predictor of CVD and stroke, but causality and the precise pathophysiological mechanism(s) of homocysteine action remain unproven. The predominant nutritional cause of raised plasma homocysteine in most healthy populations is folate insufficiency. Vitamin B12and, to a lesser extent, vitamin B6are also effective at lowering plasma homocysteine, especially after homocysteine lowering by folic acid in those individuals presenting with raised plasma homocysteine. However, riboflavin supplementation appears to be effective at lowering plasma homocysteine only in those individuals homozygous for the T allele of the C677 T polymorphism of the methylenetetrahydrofolate reductase (MTHFR) gene. This gene codes for the MTHFR enzyme that produces methyltetrahydrofolate, which, in turn, is a substrate for the remethylation of homocysteine by the vitamin B12-dependent enzyme methionine synthase. Individuals with the MTHFR 677 TT genotype are genetically predisposed to elevated plasma homocysteine, and in most populations have a markedly higher risk of CVD.

scholarly journals Influence of Methylenetetrahydrofolate Reductase Gene Polymorphisms on Homocysteine Concentrations after Nitrous Oxide Anesthesia

2008 ◽  
Vol 109 (1) ◽  
pp. 36-43 ◽  
Author(s):  
Peter Nagele ◽  
Barbara Zeugswetter ◽  
Caspar Wiener ◽  
Hansjörg Burger ◽  
Michael Hüpfl ◽  
...  
Keyword(s):  
Nitrous Oxide ◽  
Vitamin B12 ◽  
Methylenetetrahydrofolate Reductase ◽  
Elective Surgery ◽  
Plasma Concentrations ◽  
Mthfr Gene ◽  
Plasma Homocysteine ◽  
Outcome Variable ◽  
Wild Type ◽  
Oxide Anesthesia

Background Mutations in the methylenetetrahydrofolate reductase (MTHFR) gene (677C>T, 1298A>C) cause elevated plasma homocysteine concentrations and have been linked to fatal outcomes after nitrous oxide anesthesia. This study tested the hypothesis that patients with common MTHFR 677C>T or 1298A>C mutations develop higher plasma homocysteine concentrations after nitrous oxide anesthesia than wild-type patients. Methods In this prospective, observational cohort study with blinded, mendelian randomization, the authors included 140 healthy patients undergoing elective surgery. All patients received 66% nitrous oxide for at least 2 h. The main outcome variable, plasma total homocysteine, and folate, vitamin B12, and holotranscobalamin II were measured before, during, and after surgery. After completion of the study, all patients were tested for their MTHFR 677C>T or 1298A>C genotype. Results Patients with a homozygous MTHFR 677C>T or 1298A>C mutation (n = 25) developed higher plasma homocysteine concentrations (median [interquartile range], 14.9 [10.0-26.4] microm) than wild-type or heterozygous patients (9.3 [7.5-15.5] microm; n = 115). The change in homocysteine after nitrous oxide anesthesia was tripled in homozygous patients compared with wild-type (5.6 microm [+60%] vs. 1.8 microm [+22%]). Only homozygous patients reached average homocysteine levels considered abnormal (> 15 microm). Plasma 5-methyl-tetrahydrofolate concentrations increased uniformly by 20% after nitrous oxide anesthesia, indicating the inactivation of methionine synthase and subsequent folate trapping. Holotranscobalamin II concentrations remained unchanged, indicating no effect of nitrous oxide on vitamin B12 plasma concentrations. Conclusions This study shows that patients with a homozygous MTHFR 677C>T or 1298A>C mutation are at a higher risk of developing abnormal plasma homocysteine concentrations after nitrous oxide anesthesia.

scholarly journals Postgraduate Symposium The MTHFR C677T polymorphism, B-vitamins and blood pressure

2009 ◽  
Vol 69 (1) ◽  
pp. 156-165 ◽  
Author(s):  
C. P. Wilson ◽  
H. McNulty ◽  
J. M. Scott ◽  
J. J. Strain ◽  
M. Ward
Keyword(s):  
Blood Pressure ◽  
Methylenetetrahydrofolate Reductase ◽  
Mthfr C677t ◽  
Mthfr Gene ◽  
B Vitamins ◽  
Vitamin B ◽  
C677t Polymorphism ◽  
Mthfr Polymorphism ◽  
Mthfr C677t Polymorphism ◽  
B Vitamin

High blood pressure (BP) and elevated homocysteine are reported as independent risk factors for CVD and stroke in particular. The main genetic determinant of homocysteine concentrations is homozygosity (TT genotype) for the C677T polymorphism in the methylenetetrahydrofolate reductase (MTHFR) gene, typically found in approximately 10% of Western populations. The B-vitamins folate, vitamin B12and vitamin B6are the main nutritional determinants of homocysteine, with riboflavin more recently identified as a potent modulator specifically in individuals with the TT genotype. Although observational studies have reported associations between homocysteine and BP, B-vitamin intervention studies have shown little or no BP response despite decreases in homocysteine. Such studies, however, have not considered the MTHFR C677T polymorphism, which has been shown to be associated with BP. It has been shown for the first time that riboflavin is an important determinant of BP specifically in individuals with the TT genotype. Research generally suggests that 24 h ambulatory BP monitoring provides a more accurate measure of BP than casual measurements and its use in future studies may also provide important insights into the relationship between the MTHFR polymorphism and BP. Further research is also required to investigate the association between specific B-vitamins and BP in individuals with different MTHFR genotypes in order to confirm whether any genetic predisposition to hypertension is correctable by B-vitamin intervention. The present review will investigate the evidence linking the MTHFR C677T polymorphism to BP and the potential modulating role of B-vitamins.

scholarly journals Polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) gene, intakes of folate and related B vitamins and colorectal cancer: a case–control study in a population with relatively low folate intake

2008 ◽  
Vol 99 (2) ◽  
pp. 379-389 ◽  
Author(s):  
Linda Sharp ◽  
Julian Little ◽  
Nigel T. Brockton ◽  
Seonaidh C. Cotton ◽  
Lindsey F. Masson ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Carbon Metabolism ◽  
Methylenetetrahydrofolate Reductase ◽  
Case Control Study ◽  
Case Control ◽  
B Vitamins ◽  
Folate Intake ◽  
Vitamin B ◽  
One Carbon Metabolism ◽  
Control Study

Folate is key in one-carbon metabolism, disruption of which can interfere with DNA synthesis, repair, and methylation. Efficient one-carbon metabolism requires other B vitamins and the optimal activity of enzymes including 5,10-methylenetetrahydrofolate reductase (MTHFR). We report a population-based case–control study of folate intake, related dietary factors andMTHFRpolymorphisms (C677T, A1298C) and colorectal cancer in a population with relatively high colorectal cancer incidence and relatively low folate intake. A total of 264 cases with histologically confirmed incident colorectal cancer and 408 controls participated. There was no clear trend in risk with reported intakes of total, or dietary, folate, riboflavin, vitamin B12or vitamin B6, nor were there interactions between folate intake and the other B vitamins or alcohol. For C677T, risk decreased with increasing variant alleles (multivariate OR for CTv.CC = 0·77 (95 % CI 0·52, 1·16); OR for TTv.CC = 0·62 (95 % CI 0·31, 1·24)), which, although not statistically significant, was consistent with previous studies. For A1298C, compared with AA subjects, CC subjects had modest, non-significant, reduced risk (multivariate OR = 0·81 (95 % CI 0·45, 1·49)). There were significant interactions between total folate and C677T (P = 0·029) and A1298C (P = 0·025), and total vitamin B6and both polymorphisms (C677T,P = 0·016; A1298C,P = 0·033), although the patterns observed differed from previous studies. Seen against the setting of low folate intake, the results suggest that the role of folate metabolism in colorectal cancer aetiology may be more complex than previously thought. Investigation of particular folate vitamers (for example, tetrahydrofolate, 5,10-methylenetetrahydrofolate) may help clarify carcinogenesis pathways.

scholarly journals Effect of MTHFR 1298A→C and MTHFR 677C→T Genotypes on Total Homocysteine, Folate, and Vitamin B12 Plasma Concentrations in Kdiney Graft Recipients

2000 ◽  
Vol 11 (10) ◽  
pp. 1918-1925
Author(s):  
MANUELA FÖDINGER ◽  
HEIDI BUCHMAYER ◽  
GOTFRIED HEINZ ◽  
MENELAOS PAPAGIANNOPOULOS ◽  
JOSEF KLETZMAYR ◽  
...  
Keyword(s):  
Creatinine Clearance ◽  
Plasma Levels ◽  
Methylenetetrahydrofolate Reductase ◽  
Plasma Concentrations ◽  
Vitamin B ◽  
Compound Heterozygous ◽  
Kidney Graft ◽  
Linear Regression Models ◽  
Total Homocysteine ◽  
Folate And Vitamin B12

Abstract. The effect of 5,10-methylenetetrahydrofolate reductase (MTHFR) 677C→T and 1298A→C on total homocysteine (tHcy), folate and vitamin B12 levels was investigated in 733 kidney graft recipients. The six major genotype combinations were used as grouping variables, and age, gender, BMI, serum creatinine, and creatinine clearance and ln-folate, ln-vitamin B12, or logarithmus naturalis tHcy (ln-tHcy) were used as covariates in three ANCOVA and multiple stepwise linear regression models. Hyperhomocysteinemia was present in 49.7% of the patients. The allele frequency of MTHFR 677T and 1298C was 0.319 and 0.326. MTHFR genotype and all other variables were significant predictors of ln-tHcy (higher tHcy plasma levels for MTHFR 677TT/1298AA versus all other five genotype groups: P < 0.05). BMI, creatinine clearance, ln-tHcy, and MTHFR genotype influenced ln-folate (lower folate levels for MTHFR 677TT/1298AA versus all other genotype groups: P < 0.05). Creatinine clearance and ln-tHcy were the only predictors of ln-vitamin B12 levels. In a prespecified subgroup analysis (n = 496), the MTHFR genotype also influenced tHcy levels and compound heterozygous patients had significantly lower folate levels as compared with MTHFR 677CC/1298AA and 677CC/1298CC. This study shows that the MTHFR 677TT/1298AA and 677CT/1298AC genotypes are significant predictors of tHcy and folate plasma levels.

scholarly journals C1 metabolism and CVD outcomes in older adults

2011 ◽  
Vol 71 (2) ◽  
pp. 213-221 ◽  
Author(s):  
Helene McNulty ◽  
J. J. Strain ◽  
Kristina Pentieva ◽  
Mary Ward
Keyword(s):  
Folic Acid ◽  
Methylenetetrahydrofolate Reductase ◽  
Epidemiological Studies ◽  
Plasma Homocysteine ◽  
Convincing Evidence ◽  
B Vitamins ◽  
Current Evidence ◽  
High Dose ◽  
C1 Metabolism ◽  
Meta Analyses

CVD is the most common cause of death in people over 65 years. This review considers the latest evidence for a potential protective effect of C1 donors (folate and the metabolically related B-vitamins) in CVD. Such an effect may or may not be mediated via the role of these nutrients in maintaining plasma homocysteine concentrations within a desirable range. Despite predictions from epidemiological studies that lowering plasma homocysteine would reduce cardiovascular risk, several secondary prevention trials in at-risk patients published since 2004 have failed to demonstrate a benefit of homocysteine-lowering therapy with B-vitamins on CVD events generally. All these trials were performed in CVD patients with advanced disease; thus current evidence suggests that intervention with high-dose folic acid is of no benefit in preventing another event, at least in the case of heart disease. The evidence at this time, however, is stronger for stroke, with meta-analyses of randomised trials showing that folic acid reduces the risk of stroke, particularly in people with no history of stroke. Genetic studies provide convincing evidence to support a causal relationship between sub-optimal B-vitamin status and CVD. People homozygous for the common C677T variant in the gene encoding the folate-metabolising enzyme, methylenetetrahydrofolate reductase (MTHFR), typically have a 14–21% higher risk of CVD. Apart from folate, riboflavin is required as a co-factor for MTHFR. New evidence shows that riboflavin intervention results in marked lowering of blood pressure, specifically in patients with the MTHFR 677TT genotype. This novel gene–nutrient interaction may provide insights as to the mechanism that links C1 metabolism with CVD outcomes.

Phase I Clinical and Pharmacogenetic Trial of Irinotecan and Raltitrexed Administered Every 21 Days to Patients With Cancer

2001 ◽  
Vol 19 (20) ◽  
pp. 4081-4087 ◽  
Author(s):  
James P. Stevenson ◽  
Maryann Redlinger ◽  
Leo A.J. Kluijtmans ◽  
Weijing Sun ◽  
Kenneth Algazy ◽  
...  
Keyword(s):  
Methylenetetrahydrofolate Reductase ◽  
Clinical Investigation ◽  
Performance Status ◽  
Mthfr C677t ◽  
Mthfr Gene ◽  
Plasma Homocysteine ◽  
Gastrointestinal Malignancies ◽  
Patients With Cancer ◽  
Functional Polymorphisms

PURPOSE: Irinotecan and raltitrexed display schedule-dependent synergy in vitro, which supports the clinical investigation of the combination. Functional polymorphisms of the methylenetetrahydrofolate reductase (MTHFR) gene result in intracellular redistribution of folate derivatives, which may affect raltitrexed-associated cytotoxicity.PATIENTS AND METHODS: Patients with a range of solid cancers and good performance status received irinotecan as a 90-minute infusion on day 1 and raltitrexed as a 15-minute infusion on day 2, repeated every 21 days. Samples were collected for MTHFR C677T genotyping and fasting plasma homocysteine during the first cycle.RESULTS: Thirty-nine assessable patients received 127 cycles of therapy. Irinotecan doses ranged from 100 to 350 mg/m2, and raltitrexed, 1.0 to 4.0 mg/m2. Raltitrexed doses of more than 3.0 mg/m2were not tolerated and were associated with dose-limiting asthenia, diarrhea, and AST/ALT elevation. Irinotecan/raltitrexed doses of 350/3.0 mg/m2were well-tolerated; principal toxicities included neutropenia, diarrhea, and fatigue. Two partial responses were observed in patients with pretreated gastroesophageal cancers. Homozygotes with the MTHFR 677 TT polymorphism incurred significantly less raltitrexed-associated toxicity than those with either wild-type or heterozygous genotypes (P = .05). No significant differences were noted in plasma homocysteine values between the genotypic subtypes, and plasma homocysteine levels did not predict the risk of toxicity.CONCLUSION: Irinotecan and raltitrexed doses of 350 and 3.0 mg/m2are recommended for further study on a day 1, 2 schedule every 21 days. Efficacy results suggest that trials in upper and lower gastrointestinal malignancies are warranted. MTHFR C677T genotypes may be predictive of clinical raltitrexed toxicity.

Homocysteine, folate, methylene tetrahydrofolate reductase genotype and vascular morbidity in diabetic subjects

2002 ◽  
Vol 102 (6) ◽  
pp. 631-637 ◽  
Author(s):  
Joey M. KAYE ◽  
Kim G. STANTON ◽  
Vincent J. MCCANN ◽  
Samuel D. VASIKARAN ◽  
Valerie BURKE ◽  
...  
Keyword(s):  
Vascular Disease ◽  
Methylenetetrahydrofolate Reductase ◽  
Mthfr Gene ◽  
Plasma Homocysteine ◽  
Serum Folate ◽  
Type I ◽  
Cross Sectional Survey ◽  
Cross Sectional ◽  
Mthfr Genotype ◽  
Erythrocyte Folate

In the present study, the determinants of fasting plasma homocysteine in diabetic subjects were examined; whether plasma homocysteine and vascular disease are related and the influence of the C677T polymorphism in the methylenetetrahydrofolate reductase (MTHFR) gene on serum and erythrocyte folate, plasma homocysteine and vascular disease. Diabetic clinic subjects (Type I, n = 354; Type II, n = 392) were recalled for a cross-sectional survey. Standard methods were used to measure biochemical variables and to characterize vascular disease and MTHFR genotype. Plasma homocysteine was significantly and directly related to age, male sex and serum urea, and inversely related to serum folate and vitamin B12, independently in stepwise regression. When corrected for age and sex, homocysteine was significantly related to hard end points of coronary artery disease and stroke (each P<0.01), remaining significant when additionally adjusted for serum folate (P = 0.043 and P = 0.019 respectively). Serum folate was not clearly related to these events, although there was a trend to associate with the lower quintile of serum folate. The MTHFR genotype was not a determinant of plasma homocysteine, even in those in the lowest quintile of serum folate, nor of vascular disease. TT homozygosity at residue 677 was associated with elevation of total erythrocyte folate compared with both other genotypes (P<0.0001), almost certainly due to the diversion of 5,10-methylenetetrahydrofolate into derivates subsequent to the partial metabolic block that results from the MTHFR enzyme defect. In conclusion, in this clinic cohort of people with diabetes, vascular disease is related to plasma homocysteine, which is correlated with serum folate. The MTHFR genotype does not significantly influence either plasma homocysteine or vascular disease, despite it being a determinant of erythrocyte folate, which reflects its effect on folate metabolism.

scholarly journals Vitamin B-12 Status Is Inversely Associated with Plasma Homocysteine in Young Women with C677T and/or A1298C Methylenetetrahydrofolate Reductase Polymorphisms

2002 ◽  
Vol 132 (7) ◽  
pp. 1872-1878 ◽  
Author(s):  
Lynn B. Bailey ◽  
Robert L. Duhaney ◽  
David R. Maneval ◽  
Gail P.A. Kauwell ◽  
Eoin P. Quinlivan ◽  
...  
Keyword(s):  
Young Women ◽  
Methylenetetrahydrofolate Reductase ◽  
Plasma Homocysteine ◽  
Vitamin B ◽  
Vitamin B 12
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