Homocysteine synthesis is elevated but total remethylation is unchanged by the methylenetetrahydrofolate reductase 677C->T polymorphism and by dietary folate restriction in young women (original) (raw)
Related papers
2005
Background: A high plasma concentration of total homocysteine has been linked to a higher risk of cardiovascular disease. Subjects homozygous for the methylenetetrahydrofolate reductase (MTHFR) 677C→ →T mutation have depressed folate and elevated homocysteine concentrations. They may have increased folate requirements compared to subjects with CT and CC genotypes. Objective: We investigated whether MTHFR C677T genotypes differ in their associations of 1. folate intake with folate status, and 2. folate status/folate intake with plasma homocysteine concentrations. We also investigated in these three genotypes the effect of one year folic acid supplementation (800 µg/day) on serum folate and plasma homocysteine. Design: In a double blind randomised placebo-controlled trial, 815 volunteers aged 50-70 years (n= 312 CC, 378 CT and 125 TT) with homocysteine above 13 µmol/L at screening, were allocated to daily folic acid (800 µg) or placebo treatment during one year. Results: At baseline, the median folate intake was 194 µg/day and did not differ between genotypes. Subjects with the TT genotype had 13% lower levels of serum folate and 8% higher homocysteine compared with CC subjects. At an intake level above 215 µg/day (upper quartile) subjects with the TT genotype had similar homocysteine compared with subjects with the CC or CT genotypes with folate intakes below 138 µg/day (bottom quartile). This indicates a higher folate requirement of the TT genotype. After one year of folic acid supplementation homocysteine decreased by 35% in the total study population. Subjects with the TT genotype had a 4.3 µmol/L (-40%) decrease of homocysteine compared to placebo, which was significantly greater (p<0.0001) than that of subjects with the CC genotype (-3,2 µmol/L, -32%) or the CT genotype (-3.0 µmol/L, -31%). After one year supplementation, mean homocysteine of subjects with the TT, CT and CC genotypes were 9.2; 9.6 and 9.7 µmol/L respectively.
Circulation, 1996
From the Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, Mass (PFJ, AGB, IHR, JS); the NHLBI Family Heart Study, University of Utah Cardiovascular Genetics Research Clinic, Salt Lake City (RRW); the NHLBI Family Heart Study, ...
American Journal of Physiology-endocrinology and Metabolism, 2001
Folate and vitamin B 6 act in generating methyl groups for homocysteine remethylation, but the kinetic effects of folate or vitamin B 6 deficiency are not known. We used an intravenous primed, constant infusion of stable isotope-labeled serine, methionine, and leucine to investigate one-carbon metabolism in healthy control (n ϭ 5), folatedeficient (n ϭ 4), and vitamin B 6-deficient (n ϭ 5) human subjects. The plasma homocysteine concentration in folatedeficient subjects [15.9 Ϯ 2.1 (SD) mol/l] was approximately two times that of control (7.4 Ϯ 1.7 mol/l) and vitamin B6-deficient (7.7 Ϯ 2.1 mol/l) subjects. The rate of methionine synthesis by homocysteine remethylation was depressed (P ϭ 0.027) in folate deficiency but not in vitamin B6 deficiency. For all subjects, the homocysteine remethylation rate was not significantly associated with plasma homocysteine concentration (r ϭ Ϫ0.44, P ϭ 0.12). The fractional synthesis rate of homocysteine from methionine was positively correlated with plasma homocysteine concentration (r ϭ 0.60, P ϭ 0.031), and a model incorporating both homocysteine remethylation and synthesis rates closely predicted plasma homocysteine levels (r ϭ 0.85, P ϭ 0.0015). Rates of homocysteine remethylation and serine synthesis were inversely correlated (r ϭ Ϫ0.89, P Ͻ 0.001). These studies demonstrate distinctly different metabolic consequences of vitamin B6 and folate deficiencies. one-carbon metabolism; remethylation; stable isotopes; human; vitamin B 6; folate MILD ELEVATION OF PLASMA HOMOCYSTEINE is an independent risk factor for cardiovascular disease, peripheral arterial occlusive disease, stroke, and venous thrombosis (1, 2, 5, 12, 29). For example, Boushey et al. (1) calculated in a meta-analysis that the odds ratio for coronary artery disease in males for each 5 mol/l increase in plasma homocysteine is 1.6. However, it is unclear whether homocysteine is directly involved
Folate and homocysteine phenotypes: Comparative findings using research and clinical laboratory data
2009
Objectives: A low folate/high homocysteine phenotype is associated with several pathologies, including spina bifida and cardiovascular disease. Folate and total homocysteine (tHcy) measurements are used clinically to assess risk and the need for folic acid supplementation and in research to investigate the metabolic basis of disease. Red blood cell (RBC) folate, the best indicator of long-term folate status, is usually measured as "total" folate. However, different folate derivatives support distinct biochemical functions, suggesting a need to develop more precise methods. This study was designed to evaluate a method based on stable isotope dilution liquid chromatography-multiple reaction monitoring/mass spectrometry (LC-MRM/MS).
The American Journal of Clinical Nutrition, 2002
Background: Elevated plasma total homocysteine (tHcy) is a risk factor for vascular disease and neural tube defects. The polymorphism in the gene encoding 5,10-methylenetetrahydrofolate reductase (FADH 2) (MTHFR) influences the tHcy concentration and the response to tHcy-lowering therapy. Supplementation with folic acid (FA) decreases plasma tHcy, but limited data are available on the effect of 5-methyltetrahydrofolate (MTHF). Objective: We evaluated the tHcy-lowering potential of lowdose FA and of MTHF with respect to the MTHFR genotype. Design: In this randomized, placebo-controlled, double-blind study, 160 women received 400 g FA, the equimolar amount of MTHF (480 g, racemic mixture), or a placebo daily during an 8-wk treatment period. Blood samples were collected at baseline and at 4 and 8 wk. Results: Changes in plasma tHcy concentration depended on the supplemented folate derivative and the MTHFR genotype. Supplementation with FA significantly decreased tHcy concentrations by ≥ 13% in women of all 3 genotypes after both 4 and 8 wk. The greatest decrease was 20% (P < 0.05) in the women with the TT genotype after 4 wk. MTHF supplementation also decreased tHcy, but only the women with the CT genotype had a significant decrease after 4 wk (7%; P < 0.05). The largest nonsignificant reduction (15%) occurred in the women with the TT genotype after 4 wk of MTHF supplementation. Conclusions: The response to tHcy-lowering therapy is influenced by MTHFR genotype. Women with the TT genotype seem to benefit the most from supplementation with either FA or MTHF. In women with the CT or CC genotype, FA is more effective than MTHF in lowering plasma tHcy.
The Journal of nutrition, 2005
Risk factors established at young ages may set the stage for later cardiovascular disease (CVD). Elevated total homocysteine (tHcy) in blood is an emerging risk factor for CVD, yet few studies have been conducted in children, especially in the Mediterranean. We described plasma tHcy concentrations in a group of healthy Greek children and examined its relation with physiologic, metabolic, and genetic variables. Fasting blood samples were collected from 186 students, 11.6 +/- 0.4 years old, and tHcy, folate, vitamin B-12, and routine biochemistry variables in plasma were measured. The methylenetetrahydrolate reductase (MTHFR) C677T genotype was determined and anthropometric and dietary data were obtained. The distribution of tHcy was positively skewed with a median of 7.9 micromol/L (mean: 8.2 +/- 2.3 micromol/L; range: 4.4-22.2 micromol/L). tHcy was inversely related to plasma folate (r = -0.34, P < 0.0001), vitamin B-12 (r = -0.20, P = 0.008), and glucose (r = -0.15, P = 0.045). ...
The American journal of clinical nutrition, 2006
Homocysteine concentrations are influenced by vitamin status and genetics, especially several polymorphisms in folate-metabolizing genes. We examined the interactions and associations with serum total homocysteine (tHcy) and folate concentrations of polymorphisms in the following folate-metabolizing genes: methylenetetrahydrofolate reductase (MTHFR), reduced folate carrier 1 (RFC1), and glutamate carboxypeptidase II (GCPII). Healthy volunteers (436 men and 606 women; mean age: 77.9 y) were randomly selected from among residents of Oxford, United Kingdom. We determined the individual effects and interactions of the MTHFR 677C-->T, MTHFR 1298A-->C, RFC1 80G-->A, and GCPII 1561C-->T polymorphisms on serum tHcy and folate concentrations. Subjects with the MTHFR 677TT genotype had higher serum tHcy concentrations than did those with the MTHFR 677CC genotype (P < 0.001), and this effect was greater in subjects with low serum folate status (P for interaction = 0.026). The MT...
The Journal of nutrition, 2003
The C677T variant of methylenetetrahydrofolate reductase (MTHFR), a key enzyme in the remethylation of homocysteine to methionine, is a frequent genetic cause of mild hyperhomocysteinemia among individuals with low folate status. However, little is known about the influence of subject characteristics, such as age and sex, on the relation between the C677T MTHFR polymorphism and fasting plasma total homocysteine (tHcy) concentrations. The aim of the present study was to explore the influence of age and gender, together with folate status, on the association between the C677T polymorphism and tHcy concentrations. The C677T genotype was determined for 1820 participants from the fifth examination of the Framingham Offspring Study. Mean age of the participants was 56 y (range 28-82 y). The allelic distribution was not different from the Hardy-Weinberg equilibrium, with a TT frequency comparable in men and women (14%). Geometric mean tHcy was 15% higher in men than in women (P < 0.001)...
British Journal of Nutrition, 2000
The 677cytosine (c)→thymine(T) mutation identified in the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene has been frequently associated with an elevated plasma homocysteine concentration. The aim of the present study was to determine the impact of this MTHFR common mutation on plasma and erythrocyte folate (RCF) and plasma total homocysteine (tHcy) concentrations in healthy French adults. A cohort of 291 subjects living in the Paris area and participating in the Supplementation en Vitamines et Mineraux Antioxydants (SU.VI.MAX) study were analysed to assess the impact of MTHFR polymorphism 677C→T on folate status and plasma tHcy concentration. The frequency of the mutant homozygote for 677C→T polymorphism (677TT genotype) in the present cohort was 16·8%. There were significant differences in plasma tHcy between 677CC, 677CT and 677TT genotype groups. The RCF concentrations were significantly different between each genotype, the lowest levels being associated with the 677TT gen...