Homocysteine concentrations in adults with trisomy 21: effect of B vitamins and genetic polymorphisms

BACKGROUND: The effects of supplementation with B vitamins and of common polymorphisms in genes involved in homocysteine metabolism on plasma total homocysteine (tHcy) concentrations in trisomy 21 are unknown. OBJECTIVES: We aimed to determine the effects of orally administered folic acid and of folic acid combined with vitamin B-12, vitamin B-6, or both on tHcy in adults with trisomy 21. The study was also intended to analyze the possible influence of gene polymorphisms. DESIGN: One hundred sixty adults with trisomy 21 and 160 healthy, unrelated subjects aged 26 +/- 4 y were included. Plasma tHcy, red blood cell folate, serum folate, and vitamin B-12 were measured. Genotyping for the common methylenetetrahydrofolate reductase (MTHFR) 677C-->T, MTHFR 1298A-->C, cystathionine beta-synthase 844Ins68, methionine synthase 2756A-->C, methionine synthase reductase 66A-->G, and reduced folate carrier 80G-->A polymorphisms was carried out. RESULTS: The mean tHcy concentration (9.8 +/- 0.7 micromol/L) of cases who did not use vitamins was not significantly different from that of controls (9.4 +/- 0.3 micromol/L). Plasma tHcy concentrations (7.6 +/- 0.3 mmol/L) in cases who used folic acid were significantly lower than in cases who did not. Folic acid combined with vitamin B-12 did not significantly change tHcy concentrations compared with those in cases who used only folic acid. Folic acid combined with vitamins B-6 and B-12 significantly lowered tHcy (6.5 +/- 0.5 micromol/L). The difference in tHcy according to MTHFR genotype was not significant. However, tHcy concentrations were slightly higher in TT homozygotes among the controls but not among the cases. CONCLUSION: This study provides information on the relation between several polymorphisms in genes involved in homocysteine and folate metabolism in adults with trisomy 21.     

Methionine synthase reductase 66A->G polymorphism is associated with increased plasma homocysteine concentration when combined with the homozygous methylenetetrahydrofolate reductase 677C->T variant

Methylenetetrahydrofolate reductase (MTHFR) and methionine synthase reductase (MTRR) are important for homocysteine remethylation. This study was designed to determine the influence of genetic variants (MTHFR 677C-->T, MTHFR 1298A-->C, and MTRR 66A-->G), folate, and vitamin B-12 status on plasma homocysteine in women (20-30 y; n = 362). Plasma homocysteine was inversely (P < 0.0001) associated with serum folate and plasma vitamin B-12 regardless of genotype. Plasma homocysteine was higher (P < 0.05) for women with the MTHFR 677 TT/1298 AA genotype combination compared with the CC/AA, CC/AC, and CT/AA genotypes. Women with the MTHFR 677 TT/MTRR 66 AG genotype had higher (P < 0.05) plasma homocysteine than all other genotype combinations except the TT/AA and TT/GG genotypes. There were 5.4-, 4.3-, and 3.8-fold increases (P < 0.001) in risk for plasma homocysteine in the top 5, 10, and 20%, respectively, of the homocysteine distribution for subjects with the MTHFR 677 TT compared with the CC and CT genotypes. Predicted plasma homocysteine was inversely associated with serum folate (P = 0.003) and plasma vitamin B-12 (P = 0.002), with the degree of correlation dependent on MTHFR 677C-->T genotype. These data suggest that coexistence of the MTHFR 677 TT genotype with the MTRR 66A-->G polymorphism may exacerbate the effect of the MTHFR variant alone. The potential negative effect of combined polymorphisms of the MTHFR and MTRR genes on plasma homocysteine in at-risk population groups with low folate and/or vitamin B-12 status, such as women of reproductive potential, deserves further investigation.     

Plasma vitamin B-6 forms and their relation to transsulfuration metabolites in a large, population-based study

BACKGROUND: Vitamin B-6 exists in different forms; one of those forms, pyridoxal 5'-phosphate (PLP), serves a cofactor in many enzyme reactions, including the transsulfuration pathway, in which homocysteine is converted to cystathionine and then to cysteine. Data on the relations between indexes of vitamin B-6 status and transsulfuration metabolites in plasma are sparse and conflicting. OBJECTIVE: We investigated the distribution and associations of various vitamin B-6 species in plasma and their relation to plasma concentrations of transsulfuration metabolites. DESIGN: Nonfasting blood samples from 10 601 healthy subjects with a mean age of 56.4 y were analyzed for all known vitamin B-6 vitamers, folate, cobalamin, riboflavin, total homocysteine, cystathionine, total cysteine, methionine, and creatinine. All subjects were genotyped for the methylenetetrahydrofolate reductase (MTHFR) 677C-->T polymorphism. RESULTS: Plasma concentrations of the main vitamin B-6 vitamers--PLP, pyridoxal, and 4-pyridoxic acid--were strongly correlated. Among the vitamin B-6 vitamers, PLP showed the strongest and most consistent inverse relation to total homocysteine and cystathionine, but the dose response was different for the 2 metabolites. The PLP-total homocysteine relation was significant only in the lowest quartile of the vitamin B-6 distribution and was strongest in subjects with the MTHFR 677TT genotype, whereas cystathionine showed a graded response throughout the range of vitamin B-6 vitamer concentrations, and the effect was not modified by the MTHFR 677C-->T genotype. CONCLUSION: This large population-based study provided precise estimates of the relation between plasma concentrations of vitamin B-6 forms and transsulfuration metabolites as modified by the MTHFR 677C-->T genotype.     

Vitamin B-12 status is inversely associated with plasma homocysteine in young women with C677T and/or A1298C methylenetetrahydrofolate reductase polymorphisms

Methylenetetrahydrofolate reductase (MTHFR) polymorphisms may negatively influence one-carbon metabolism and increase health risks in women of reproductive age. The effect of MTHFR single nucleotide polymorphisms at bp 677 and/or 1298 and differences in folate and vitamin B-12 status on plasma homocysteine concentration in women of reproductive age (20-30 y; n = 186) were investigated. From the multivariate regression model, homozygotes (n = 23) for the C677T MTHFR variant had plasma homocysteine concentrations that were higher (P < 0.05) than those observed in the other 5 genotype groups, including those who were heterozygous for both variants (677CT/1298AC; n = 32). Plasma homocysteine was negatively associated with plasma vitamin B-12 concentration (P = 0.015) and serum folate (P = 0.049), with the degree of correlation between plasma vitamin B-12 and homocysteine concentrations dependent on MTHFR genotype. The C677T and A1298C MTHFR polymorphisms were significant predictors (P < 0.05) of plasma homocysteine when regression analysis was used to model plasma homocysteine concentration as a function of genotype, supplement use, serum folate and plasma vitamin B-12 concentration. Plasma homocysteine decreased as vitamin B-12 concentration increased (P = 0.0005) in individuals who were heterozygous for both the C677T and A1298C variants with nonsignificant trends (P = 0.114-0.128) in individuals homozygous for either the C677T or A1298C variants. In contrast, within the group of individuals with the wild-type genotype for both the C677T and A1298C MTHFR variants, homocysteine was not associated with changes in plasma vitamin B-12 concentrations. These data suggest that enhancing vitamin B-12 status may significantly decrease homocysteine in young women with C677T and/or A1298C MTHFR polymorphisms, even when vitamin B-12 concentrations are within the normal range.     

Interactions among polymorphisms in folate-metabolizing genes and serum total homocysteine concentrations in a healthy elderly population

BACKGROUND: Homocysteine concentrations are influenced by vitamin status and genetics, especially several polymorphisms in folate-metabolizing genes. OBJECTIVE: 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). DESIGN: 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. RESULTS: 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 MTHFR 1298A-->C, RFC1 80G-->A, and GCPII 1561C-->T polymorphisms had no individual effects on serum tHcy or folate concentrations. There was no interactive effect of the MTHFR 677C-->T and MTHFR 1298A-->C polymorphisms on tHcy concentrations. An interaction (P = 0.05) was observed between the MTHFR 677TT and RFC1 80GG genotypes, whereby persons with this genotype combination had a mean (+/-SEM) serum tHcy concentration (18.5 +/- 1.2 micromol/L) that was 5.1 micromol/L greater than the mean value of 13.4 +/- 0.2 micromol/L for the whole population. CONCLUSIONS: Folate and tHcy concentrations were not affected individually by the MTHFR 1298A-->C, RFC1 80G-->A, or GCPII 1561C-->T polymorphisms or by combinations of the MTHFR 677C-->T and MTHFR 1298A-->C genotypes. An interaction between the MTHFR 677TT and RFC1 80GG genotypes was observed whereby persons with this combination had higher serum tHcy.     

Prevalence of methylenetetrahydrofolate reductase 677T and 1298C alleles and folate status: a comparative study in Mexican, West African, and European populations

BACKGROUND: Methylenetetrahydrofolate reductase (MTHFR) 677C-->T polymorphism is heterogeneously distributed worldwide, with the highest and lowest frequencies of the T allele in Mexico and Africa, respectively, and a south-to-north gradient in Europe. Distribution of MTHFR 1298A-->C is less well known. It has been hypothesized that 677T frequency could result in part from gene-nutrient interactions. OBJECTIVE: The objective was to compare the association of 677T and 1298C alleles with plasma concentrations of homocysteine, folate, and vitamin B-12 in geographical areas with contrasting 677T allele frequencies. DESIGN: Healthy young adults (n = 1277) were recruited in Mexico City, the West African countries of Bénin and Togo, France, and Sicily (Italy). Homocysteine, folate, and vitamin B-12 were measured in plasma, and MTHFR polymorphisms were measured in genomic DNA. RESULTS: Mexico City and Sicily reported the highest and Bénin and Togo reported the lowest plasma concentrations of folate. Mexico City had the highest 677T allele prevalence and the lowest influence of 677TT genotype on homocysteine, whereas the opposite was observed in Africa. The prevalence of the 1298C allele was lowest in the Mexicans and Africans and highest in the French. The percentage of the 677T genotype was significantly associated with the folate concentrations in 677CC carriers in a univariate analysis (R = 0.976; 95% CI: 0.797, 0.996; P < 0.0002) and in a multiple regression model that included homocysteine, vitamin B-12, and age (P = 0.0002). CONCLUSION: Our data agree with the hypothesis of a gene-nutrient interaction between MTHFR 677C-->T polymorphism and folate status that may confer a selective advantage of TT-homozygous genotype when dietary intake of folate is adequate, at least in the areas studied.     

Plasma homocysteine concentrations in Greek children are influenced by an interaction between the methylenetetrahydrofolate reductase C677T genotype and folate status

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). An interaction between the MTHFR genotype and plasma folate on tHcy was detected (P = 0.047). Specifically, the homozygous mutant TT genotype was associated with higher tHcy only in children with lower plasma folate (< 19.9 nmol/L), (P = 0.012). In our sample of healthy Greek children, plasma tHcy concentrations were higher than values reported in children of Northern European descent and were associated with folate, vitamin B-12, and glucose in plasma. The results also show that, similar to adults, plasma folate concentration is important in determining the contribution of the MTHFR C677T mutation to tHcy concentrations in children.     

High plasma homocysteine is associated with the risk of coronary artery disease independent of methylenetetrahydrofolate reductase 677C-->T genotypes

Hyperhomocysteinemia is an independent risk factor for coronary artery disease (CAD). The aim of this study was to investigate the relations between the methylenetetrafolate reductase (MTHFR) 677C-->T genotypes, B-vitamins (folate, vitamin B-12 and B-6), homocysteine and the risk of CAD. In this case-control study, patients who were identified by cardiac catheterization as having at least 50% stenosis of one major coronary artery were assigned to the case group (n=121). Healthy individuals with normal blood biochemical values were assigned to the control group (n=155). Healthy subjects were matched to case subjects for age. The concentrations of plasma homocysteine, serum folate, vitamin B-12, plasma pyridoxal 5'- phosphate (PLP) and MTHFR 677C-->T gene polymorphism were obtained. The T-allele carriers had significantly higher plasma homocysteine concentration compared to subjects with the 677CC genotype. The MTHFR 677C-->T genotypes were associated with plasma homocysteine after adjusting for various potential risk factors in the case and pooled groups. The MTHFR genotypes were found to have no associations with the risk of CAD. However, plasma homocysteine (>or= 12.5 micromol/L) (OR, 3.49; 95% CI, 1.23-9.88) had a significant association with increased risk of CAD even after additionally adjusted folate status. High plasma homocysteine concentration had a direct effect on the risk of CAD independent of MTHFR 677C-->T genotypes.     

Phenotypic expression of the methylenetetrahydrofolate reductase 677C-->T polymorphism and flavin cofactor availability in thyroid dysfunction

BACKGROUND: The 5,10-methylenetetrahydrofolate reductase gene (MTHFR) 677C-->T polymorphism modifies the risk of coronary artery disease and colon cancer and is related to plasma concentrations of total homocysteine (tHcy). Riboflavin status modifies the metabolic effect of the polymorphism, and thyroid hormones increase the synthesis of flavin cofactors. OBJECTIVE: The aim of the study was to investigate the phenotypic expression of the MTHFR 677C-->T polymorphism in terms of plasma tHcy concentrations in patients with thyroid dysfunction. DESIGN: The study population consisted of 182 patients with hyperthyroidism. We studied plasma tHcy in relation to MTHFR genotype, riboflavin, and folate before and during 6 mo of treatment with antithyroid drugs. RESULTS: Before treatment, tHcy was higher in patients with the mutant enzyme than in those with the wild-type enzyme. A genotype effect was observed only at low riboflavin or folate concentrations (P T polymorphism, possibly by modifying the availability of flavin cofactors.     

Transcobalamin 776C->G polymorphism negatively affects vitamin B-12 metabolism

BACKGROUND: A common genetic polymorphism [transcobalamin (TC) 776C-->G] may affect the function of transcobalamin, the protein required for vitamin B-12 cellular uptake and metabolism. Remethylation of homocysteine is dependent on the production of 5-methyltetrahydrofolate and adequate vitamin B-12 for the methionine synthase reaction. OBJECTIVES: The objectives were to assess the influence of the TC 776C--> G polymorphism on concentrations of the transcobalamin-vitamin B-12 complex (holo-TC) and to determine the combined effects of the TC 776C-->G and methylenetetrahydrofolate reductase (MTHFR) 677C-->T polymorphisms and vitamin B-12 status on homocysteine concentrations. DESIGN: Healthy, nonpregnant women (n = 359; aged 20-30 y) were screened to determine plasma vitamin B-12, serum holo-TC, and plasma homocysteine concentrations and TC 776C-->G and MTHFR 677C-->T genotypes. RESULTS: The serum holo-TC concentration for women with the variant TC 776 GG genotype was significantly different (P = 0.0213) from that for subjects with the CC genotype (74 +/- 37 and 87 +/- 33 pmol/L, respectively). An inverse relation was observed between plasma homocysteine concentrations and both serum holo-TC (P G polymorphism negatively affects the serum holo-TC concentration and provide additional evidence that vitamin B-12 status modulates the homocysteine concentration in this population.     

5,10-methylenetetrahydrofolate reductase common mutations, folate status and plasma homocysteine in healthy French adults of the Supplementation en Vitamines et Mineraux Antioxydants (SU.VI.MAX) cohort

The 677cytosine 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 genotype. When segregated by gender, no differences in tHcy between homozygous 677TT, heterozygous 677CT and wild-type 677CC genotype groups in women were observed. The fasting tHcy in women was unrelated to the 677C-->T mutation. However, tHcy was significantly increased in men with the homozygous 677TT genotype. We also analysed the possible implication of a second new MTHFR polymorphism (1298A-->C) in subjects with mild hyperhomocysteinaemia (4th quartile of homocysteinaemia; tHcy >11.1 micromol/l). The polymorphism 1298A-->C did not have a notable effect on tHcy or on the RCF levels. Our observations confirm a relatively high frequency of the 677TT genotype in the French population. Women with this genotype did not show the same increase in tHcy observed in men. In the present study dietary folate intake was not measured. Thus, the interaction of dietary folate with the MTHFR genotype in the French population needs further study.     

The methylenetetrahydrofolate reductase 677C->T polymorphism and dietary folate restriction affect plasma one-carbon metabolites and red blood cell folate concentrations and distribution in women

Whether folate status and the methylenetetrahydrofolate reductase (MTHFR) 677C-->T polymorphism interact to affect methionine-cycle metabolite concentrations is uncertain. We evaluated the effects of dietary folate restriction on relations among folate status indices and plasma concentrations of methionine cycle metabolites in women with the MTHFR 677 C/C and T/T genotypes. Healthy, normohomocysteinemic women (n = 18; 20-30 y old) of adequate B vitamin status, and equally divided according to MTHFR 677C-->T genotype (9 C/C and 9 T/T) were recruited. Folate status indices and methionine cycle metabolites were measured in blood samples collected at baseline and after 7 wk of dietary folate restriction (115 microg dietary folate equivalents/d). Significant negative correlations between plasma total homocysteine concentrations and total or 5-methyl folate concentrations (P = 0.041 and 0.023, respectively) in RBCs were found only in T/T subjects. Formylated folates were detected in RBCs of T/T subjects only, and their abundance was predictive of plasma total homocysteine concentration despite no significant alteration by folate restriction. Plasma concentrations of S-adenosylmethionine and S-adenosylhomocysteine were not significantly affected by dietary folate restriction and the MTHFR 677 T/T genotype. In conclusion, plasma total homocysteine concentrations in subjects with the MTHFR 677 T/T genotype were inversely related to 5-methyl folate concentrations and directly related to formylated folate concentrations in RBCs, even though the latter were not significantly affected by moderate folate restriction.     

Alcohol intake and methylenetetrahydrofolate reductase polymorphism modify the relation of folate intake to plasma homocysteine

BACKGROUND: Folate intake increases plasma folate and reduces total homocysteine (tHcy) concentrations, which may lower coronary artery disease (CAD) and cancer risks. Folate metabolism may be altered by alcohol intake and 2 common polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) gene, 677C-->T and 1298A-->C. OBJECTIVE: We examined whether the associations between folate intake and plasma folate and tHcy concentrations were modified by alcohol intake or variations in the MTHFR gene. DESIGN: We conducted a cross-sectional analysis among 988 women by using multivariate linear regression models to estimate mean plasma tHcy and folate concentrations. Folate intake was the sum of food and supplemental sources. RESULTS: We observed an inverse association between folate intake and tHcy, which was modified by alcohol intake (P for interaction = 0.04) and MTHFR677 genotype (P for interaction = 0.05) but not by MTHFR1298 genotype (P for interaction = 0.97). In the lowest quintile of folate intake, moderate drinkers (>/=15 g alcohol/d) had significantly higher tHcy concentrations (15.2 +/- 2.9 nmol/mL) than did light drinkers (11.3 +/- 0.7 nmol/mL) and nondrinkers (11.0 +/- 0.8 nmol/mL). However, the reduction in tHcy between the highest and lowest quintiles of folate intake was significantly greater in moderate drinkers (-6.6 nmol/mL) than in light drinkers (-2.3 nmol/mL) and nondrinkers (-2.1 nmol/mL). The elevated tHcy in women with low folate intake who also consumed moderate amounts of alcohol was even higher (22.4 +/- 4.8 nmol/mL) in the presence of the variant MTHFR677 allele. The positive association between folate intake and plasma folate was somewhat modified by alcohol intake (P for interaction = 0.08) but not by either MTHFR genotype. CONCLUSIONS: Moderate alcohol intake and low MTHFR activity have adverse effects on tHcy, but those effects may be overcome by sufficient folate intake.     

The glycine N-methyltransferase (GNMT) 1289 C->T variant influences plasma total homocysteine concentrations in young women after restricting folate intake

Glycine N-methyltransferase (GNMT) is a key regulatory protein in folate metabolism, methionine availability, and transmethylation reactions. Perturbations in GNMT may lead to aberrations in homocysteine metabolism, a marker of numerous pathologies. The primary objective of this study was to examine the influence of the GNMT 1289 C-->T alone, and in combination with the methylenetetrahydrofolate reductase (MTHFR) 677 C-->T variant, on plasma total homocysteine concentrations in healthy young women (n = 114). Plasma total homocysteine was measured at baseline (wk 0) and after 2 wk of controlled folate restriction (135 microg/d as dietary folate equivalents). Plasma homocysteine concentrations did not differ among the GNMT C1289T genotypes at baseline. However, after folate restriction, women with the GNMT 1289 TT genotype (n = 16) had higher (P = 0.019) homocysteine concentrations than women with the CT (n = 51) or CC (n = 47) genotype. The influence of the GNMT 1289 C-->T variant on homocysteine was dependent on the MTHFR C677T genotype. In subjects with the MTHFR 677 CC genotype, homocysteine was greater (P < or = 0.05) for GNMT 1289 TT subjects relative to 1289 CT or CC subjects. However, in subjects with the MTHFR 677 TT genotype, plasma homocysteine concentrations did not differ among the GNMT C1289T genotypes. Overall, these data suggest that the GNMT 1289 C-->T polymorphism influences plasma homocysteine and is responsive to folate intake.     

Effect of the methylenetetrahydrofolate reductase 677C-->T mutation on the relations among folate intake and plasma folate and homocysteine concentrations in a general population sample

BACKGROUND: Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme in folate and homocysteine metabolism. The common MTHFR 677C-->T polymorphism decreases the enzyme's activity. OBJECTIVE: The objective of the study was to assess the effect of the polymorphism on the relations among folate intake, plasma folate concentration, and total plasma homocysteine (tHcy) concentration. DESIGN: The design was a cross-sectional analysis in a random sample (n = 2051) of a Dutch cohort (aged 20-65 y). RESULTS: At a low folate intake (166 micro g/d), folate concentrations differed significantly among the genotypes (7.1, 6.2, and 5.4 nmol/L for the CC, CT, and TT genotypes, respectively; P for all comparisons < 0.05). At a high folate intake (250 microg/d), folate concentrations in CT and CC subjects did not differ significantly (8.3 and 8.6 nmol/L, respectively, but were significantly higher (P = 0.2) than those in TT subjects (7.3 nmol/L; P = 0.04). At a low folate concentration (4.6 nmol/L), TT subjects had a significantly higher (P = 0.0001) tHcy concentration than did CC and CT subjects (20.3 compared with 15.0 and 14.1 micromol/L, respectively), whereas at a high folate concentration (11.9 nmol/L), the tHcy concentration did not differ significantly between genotypes (P > 0.2; <13.1 for all genotypes). The relation between folate intake and tHcy concentration had a pattern similar to that of the relation between plasma folate and tHcy concentrations. CONCLUSIONS: At any folate intake level, TT subjects have lower plasma folate concentrations than do CT and CC subjects. Yet, at high plasma folate concentrations, tHcy concentrations in TT subjects are as low as those in CT and CC subjects.     

Prevalence and effects of gene-gene and gene-nutrient interactions on serum folate and serum total homocysteine concentrations in the United States: findings from the third National Health and Nutrition Examination Survey DNA Bank

BACKGROUND: Abnormalities of folate and homocysteine metabolism are associated with a number of pediatric and adult disorders. Folate intake and genetic polymorphisms encoding folate-metabolizing enzymes influence blood folate and homocysteine concentrations, but the effects and interactions of these factors have not been studied on a population-wide basis. OBJECTIVE: The objective was to assess the prevalence of these genetic polymorphisms and their relation to serum folate and homocysteine concentrations. DESIGN: DNA samples from 6793 participants in the third National Health and Nutrition Examination Survey (NHANES III) during 1991-1994 were genotyped for polymorphisms of genes coding for folate pathway enzymes 5,10-methylenetetrahydrofolate reductase (MTHFR) 677C-->T and 1298A-->C, methionine synthase reductase (MTRR) 66A-->G, and cystathionine-beta-synthase 844ins68. The influence of these genetic variants on serum folate and homocysteine concentrations was analyzed by age, sex, and folate intake in 3 race-ethnicity groups. RESULTS: For all race-ethnicity groups, serum folate and homocysteine concentrations were significantly related to the MTHFR 677C-->T genotype but not to the other polymorphisms. Persons with the MTHFR 677 TT genotype had a 22.1% (95% CI: 14.6%, 28.9%) lower serum folate and a 25.7% (95% CI: 18.6%, 33.2%) higher homocysteine concentration than did persons with the CC genotype. Moderate daily folic acid intake (mean: 150 microg/d; 95% CI: 138, 162) significantly reduced the difference in mean homocysteine concentrations between those with the MTHFR 677 CC and TT genotypes. We found a significant interaction between MTHFR 677C-->T and MTRR 66A-->G on serum homocysteine concentrations among non-Hispanic whites. CONCLUSIONS: The MTHFR 677C-->T polymorphism was associated with significant differences in serum folate and homocysteine concentrations in the US population before folic acid fortification. The effect of MTHFR 677C-->T on homocysteine concentrations was reduced by moderate daily folic acid intake.     

The relationship between riboflavin and plasma total homocysteine in the Framingham Offspring cohort is influenced by folate status and the C677T transition in the methylenetetrahydrofolate reductase gene

Methylenetetrahydrofolate reductase (MTHFR) catalyzes the synthesis of 5-methyltetrahydrofolate, the methyl donor for remethylation of homocysteine to methionine. The C677T MTHFR polymorphism is associated with mild hyperhomocysteinemia, but only in the presence of low folate status. Because MTHFR contains flavin adenine dinucleotide (FAD) as a prosthetic group, riboflavin status may also influence homocysteine metabolism. The objective of this study was to examine the association between riboflavin status and fasting plasma total homocysteine (tHcy) concentration while also considering MTHFR C677T genotype and folate status. The study was conducted using fasting plasma samples (n = 450) from the fifth examination of the Framingham Offspring Study cohort. All persons with the TT genotype and age- and sex-matched sets of individuals with the CT and CC genotypes were selected for determination of plasma riboflavin and flavin mono- and dinucleotide levels. Plasma riboflavin was associated with tHcy concentrations, but the association was largely confined to persons with plasma folate <12.5 nmol/L and TT genotype. In these persons, the mean tHcy among individuals with riboflavin levels <6.89 nmol/L was 14.5 micromol/L, whereas the mean tHcy for those with riboflavin > or = 11 nmol/L was 11.6 micromol/L (P-trend <0.03). Plasma flavin nucleotides were unrelated to tHcy concentrations. Our data suggest that riboflavin status may affect homocysteine metabolism, but only in a small segment of the population who have both low folate status and are homozygotes for the MTHFR C677T mutation.     

The effect of MTHFR(C677T) genotype on plasma homocysteine concentrations in healthy children is influenced by gender

OBJECTIVE: To explore the influence of gender, together with folate status, on the relation between the common methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism and plasma total homocysteine (tHcy) concentrations in healthy children. DESIGN: Cross-sectional study by face-to-face interview.Setting and subjects:A total of 186 sixth-grade students participated from twelve randomly selected primary schools in Volos, Greece. METHODS: Fasting tHcy, folate, and vitamin B(12) were measured in plasma. The MTHFR genotypes were determined. Anthropometric and dietary intake data by 24-h recall were collected. RESULTS: Geometric means for plasma tHcy, plasma folate and energy-adjusted dietary folate did not differ between females and males. The homozygous mutant TT genotype was associated with higher tHcy only in children with lower plasma folate concentrations (<19.9 nmol/l, P = 0.012). As a significant gender interaction was observed (P = 0.050), we stratified the lower plasma folate group by gender and found that the association between the genotype and tHcy was restricted to males (P = 0.026). Similar results were obtained when folate status was based on estimated dietary folate. Specifically, only TT males that reported lower dietary folate consumption (<37 microg/MJ/day) had tHcy that was significantly higher than tHcy levels of C-allele carriers (P = 0.001). CONCLUSIONS: Under conditions of lower folate status (as estimated by either plasma concentration or reported dietary consumption), gender modifies the association of the MTHFR(C677T) polymorphism with tHcy concentrations in healthy children. SPONSORSHIP: Kellog Europe.     

Folate intake at RDA levels is inadequate for Mexican American men with the methylenetetrahydrofolate reductase 677TT genotype

Since the establishment of the 1998 folate recommended dietary allowance (RDA), the methylenetetrahydrofolate reductase (MTHFR) 677C-->T variant has emerged as a strong modifier of folate status. This controlled feeding study investigated the adequacy of the RDA, 400 microg/d as dietary folate equivalents (DFE), for Mexican American men with the MTHFR 677CC or TT genotype. Because of the interdependency between folate and choline, the influence of choline intake on folate status was also assessed. Mexican American men (n = 60; 18-55 y) with the MTHFR 677CC (n = 31) or TT (n = 29) genotype consumed 438 microg DFE/d and total choline intakes of 300, 550 (choline adequate intake), 1100, or 2200 mg/d for 12 wk. Folate status response was assessed via serum folate (SF), RBC folate, plasma total homocysteine (tHcy), and urinary folate. SF decreased (P < 0.001) 66% to 7.9 +/- 0.7 nmol/L (means +/- SEM) in men with the 677TT genotype and 62% to 11.3 +/- 0.9 nmol/L in the 677CC genotype. Plasma tHcy increased (P < 0.0001) 170% to 31 +/- 3 micromol/L in men with the 677TT genotype and 18% to 11.6 +/- 0.3 micromol/L in the 677CC genotype. At the end of the study, 34% (677TT) and 16% (677CC) had SF concentrations <6.8 nmol/L and 79% (677TT) and 7% (677CC) had tHcy concentrations >14 micromol/L. Choline intake did not influence the response of the measured variables. These data showed that the folate RDA is not adequate for men of Mexican descent, particularly for those with the MTHFR 677TT genotype, and demonstrated a lack of influence of choline intake on the folate status variables measured in this study.     

Impaired functioning of thermolabile methylenetetrahydrofolate reductase is dependent on riboflavin status: implications for riboflavin requirements

BACKGROUND: Methylenetetrahydrofolate reductase (MTHFR; EC 1.7.99.5) supplies the folate needed for the metabolism of homocysteine. A reduction in MTHFR activity, as occurs in the homozygous state for the 677C-->T (so-called thermolabile) enzyme variant (TT genotype), is associated with an increase in plasma total homocysteine (tHcy). OBJECTIVE: In vitro studies suggest that the reduced activity of thermolabile MTHFR is due to the inappropriate loss of its riboflavin cofactor. We investigated the hypothesis that MTHFR activity in the TT genotype group is particularly sensitive to riboflavin status. DESIGN: We studied tHcy and relevant B-vitamin status by MTHFR genotype in a cross-sectional study of 286 healthy subjects aged 19-63 y (median: 27 y). The effect of riboflavin status was examined by dividing the sample into tertiles of erythrocyte glutathionine reductase activation coefficient, a functional index of riboflavin status. RESULTS: Lower red blood cell folate (P = 0.0001) and higher tHcy (P = 0.0082) concentrations were found in the TT group than in the heterozygous (CT) or wild-type (CC) groups. However, these expected relations in the total sample were driven by the TT group with the lowest riboflavin status, whose mean tHcy concentration (18.09 micromol/L) was almost twice that of the CC or CT group. By contrast, adequate riboflavin status rendered the TT group neutral with respect to tHcy metabolism. CONCLUSIONS: The high tHcy concentration typically associated with homozygosity for the 677C-->T variant of MTHFR occurs only with poor riboflavin status. This may have important implications for governments considering new fortification policies aimed at the prevention of diseases for which this genotype is associated with increased risk.