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.     

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.     

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.     

Polymorphisms in cytoplasmic serine hydroxymethyltransferase and methylenetetrahydrofolate reductase affect the risk of cardiovascular disease in men

Genetic variation in folate-regulating enzymes contributes to the risk of cardiovascular disease (CVD). The cytoplasmic serine hydroxymethyltransferase (cSHMT) enzyme is proposed to regulate a key metabolic intersection in folate metabolism. We hypothesized that a variant in cSHMT (cSHMT 1420C-->T) affects CVD risk, and that the effect depends on a linked step in the metabolic pathway catalyzed by methylenetetrahydrofolate reductase (MTHFR). A nested case-control study of incident CVD was conducted within the all-male Normative Aging Study cohort. Of the incident CVD cases, 507 had DNA samples; 2 controls/case were selected by risk set sampling (matched on age and birth year). A significant gene-gene interaction (P-values 0.0013, 0.0064) was found between MTHFR and cSHMT, and there was little or no change in the coefficients in covariate-adjusted models. The effect of MTHFR 677C-->T genotype on CVD risk varied by cSHMT 1420C-->T genotype. Among men with cSHMT 1420C-->T TT genotype, the odds ratios (OR) for CVD risk for MTHFR 677C-->T CT and TT genotypes compared with the MTHFR 677C-->T CC genotype were 3.6 (95% CI, 1.7-7.8) and 10.6 (95% CI, 2.5-46.0), respectively. Among men with the cSHMT 1420C-->T CC/CT genotype, the corresponding ORs were 1.0 (95% CI, 0.8-1.2) and 1.3 (95% CI, 0.9-1.8). Plasma total homocysteine concentrations were highest in the subgroup of men with both polymorphisms, MTHFR 677C-->T TT and cSHMT 1420C-->T TT, consistent with a higher risk of CVD in this subgroup. A more complete understanding of the molecular mechanism awaits identification of the functional effect of the polymorphism.     

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.     

The effect of 677C-->T and 1298A-->C mutations on plasma homocysteine and 5,10-methylenetetrahydrofolate reductase activity in healthy subjects

We have studied the effect of common mutations (677C-->T and 1298A-->C) of the methylenetetrahydrofolate reductase (MTHFR) gene in sixty-six healthy French subjects, aged 27-47 years. Serum folate, vitamin B12, and plasma total homocysteine were measured as well as the specific activity of MTHFR in lymphocytes. The frequency of subjects homozygous for the 677TT genotype was 18%, and that of those homozygous for the 1298CC genotype was 12.5%. The frequency of individuals heterozygous for both mutations was 23.5%. The 1298A-->C mutation was associated with decreased MTHFR specific activity in subjects with both 677CC and 677CT genotypes. This activity was 60% for the 677CC/1298AC genotype and 52% for the 677CC/1298CC genotype when compared with the MTHFR specific activity of the 677CC/1298AA genotype. Heterozygotes for both mutations (677CT/1298AC genotype) had 36% of the reference specific activity. Although homocysteine levels in 677TT and 1298CC genotype subjects were higher than for other genotypes, no significant differences were observed among different genotypes. This may be due to high serum folate level in our samples, and suggests that folate therapy may be useful to prevent hyperhomocysteinaemia in homozygous mutant subjects.     

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.     

Folate status response to controlled folate intake is affected by the methylenetetrahydrofolate reductase 677C-->T polymorphism in young women

This study was designed to evaluate the effect of the methylenetetrahydrofolate reductase (MTHFR) 677C-->T polymorphism on folate and homocysteine response in non-Hispanic women consuming a low folate diet followed by a diet providing the Recommended Dietary Allowance (RDA) for folate. Women (aged 20-30 y old) with either the TT (n = 19) or CC (n = 22) MTHFR 677C-->T genotype participated in a folate depletion-repletion study (7 wk, 115 microg dietary folate equivalents (DFE)/d; 7 wk, 400 microg DFE/d). Overall serum folate decreased (P < 0.0001) during depletion and increased (P < 0.0001) during repletion with lower (P = 0.03) postdepletion serum folate in women with the TT versus CC genotype. Folate status was low (serum folate < 13.6 nmol/L) in more women with the TT (59%) compared with the CC genotype (15%) postdepletion. Red blood cell folate for all subjects decreased during depletion (P < 0.0001) and repletion (P = 0.02) with lower (P = 0.04) red blood cell folate in women with the TT compared with the CC genotype postrepletion. Homocysteine increased (P < 0.0001) for both genotype groups postdepletion and decreased (P = 0.02) postrepletion for the CC genotype group only. Homocysteine concentrations tended to be higher (P = 0.09) in the TT versus CC genotype group postdepletion and postrepletion. These data suggest that the MTHFR 677C-->T polymorphism negatively affects the folate and homocysteine response in women consuming low folate diets followed by repletion with the RDA. These results may be important when evaluating the impact of the MTHFR 677C-->T polymorphism in countries in which low folate diets are chronically consumed.     

Does the interaction between maternal folate intake and the methylenetetrahydrofolate reductase polymorphisms affect the risk of cleft lip with or without cleft palate?

Periconceptional folic acid supplementation may reduce the risk of cleft lip with or without cleft palate (CL(P)). Polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) gene reduce availability of 5-methyltetrahydrofolate, the predominant circulating form of folate. To determine the effect of MTHFR C677T and MTHFR A1298C genotypes and haplotypes on CL(P) risk and the interaction with maternal periconceptional dietary folate and folic acid supplement intake, the authors conducted a case-control triad study in the Netherlands (1998-2000) among 179 CL(P) and 204 control families. Infant and parental MTHFR C677T and MTHFR A1298C genotypes and haplotypes were not associated with CL(P) risk in the case-control and transmission disequilibrium test analyses. Mothers carrying the MTHFR 677TT genotype and who either did not use folic acid supplements periconceptionally or had a low dietary folate intake, or both, had an increased risk of delivering a CL(P) child (odds ratio (OR) = 5.9, 95% confidence interval (CI): 1.1, 30.9; OR = 2.8, 95% CI: 0.7, 10.5; OR = 10.0, 95% CI: 1.3, 79.1, respectively). No supplement use, low dietary folate intake, and maternal MTHFR 1298CC genotype increased the risk of CL(P) offspring almost sevenfold (OR = 6.5, 95% CI: 1.4, 30.2). Thus, the detrimental effect of low periconceptional folate intake on the risk of giving birth to a CL(P) child was more pronounced in mothers with the MTHFR 677TT or MTHFR 1298CC genotype.     

The interaction between MTHFR 677 C-->T genotype and folate status is a determinant of coronary atherosclerosis risk

The 677 C-->T polymorphism in the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene interacts with folate status in determining elevated total plasma levels of homocysteine, a risk factor for coronary atherosclerotic disease (CAD). The present study had the following goals: 1) to define the 677 C-->T genotype-specific threshold values of both plasma and RBC folate, associated with hyperhomocysteinemia (>15 micro mol/L); and 2) to determine the risk of CAD among subjects with levels of folate below the genotype-specific threshold considered at risk for hyperhomocysteinemia. We examined 655 subjects, with (433) or without (222) angiographically documented CAD. The MTHFR 677 C-->T genotype-specific threshold values of plasma folate corresponded to the 40th, 30th and 10th percentile in the TT, CT and CC genotype, respectively. A multivariate logistic regression analysis showed that the risk of CAD among subjects with plasma folate levels below the genotype-specific thresholds was 1.6 (95% CI, 1.04-2.46). Similar results were obtained when RBC folate was considered as a measure of folate status (odds ratio = 1.8, 95% CI, 1.03-3.15). A gene-nutrient interaction that defines a higher risk for CAD is determined by folate levels below specific thresholds, which differ depending on the MTHFR 677 C-->T genotype.     

Dietary and genetic determinants of homocysteine levels among Mexican women of reproductive age

OBJECTIVE: To evaluate the independent and joint effects of dietary folate, vitamin B(12) consumption and methylenetetrahydrofolate reductase (MTHFR) polymorphisms (677C>T and 1298A>C) on the circulating folate and homocysteine (Hcy) levels among Mexican women of reproductive age. DESIGN: A cross-sectional, population-based study. SUBJECTS: The first 130 healthy non-pregnant women (aged 16-34 years) who agreed to participate in a reproductive cohort in Morelos, Mexico. MAIN OUTCOME MEASUREMENTS: Dietary intakes of vitamin B(12) and folate were estimated using a semiquantitative food frequency questionnaire. MTHFR 677C>T and 1298A>C polymorphisms were ascertained using the PCR-based method. Serum levels of Hcy and folate were determined using high-performance liquid chromatography and radioimmunoassay, respectively. RESULTS: Genotype frequencies for the MTHFR 677C>T polymorphism were 21.5% (CC), 52.3% (CT) and 26.2% (TT) among Mexican women. Of the population, 22% had the MTHFR 1298AC genotype, while no individual carried the 1298CC genotype. We observed an increased level of Hcy among carriers of the 677TT genotype, compared to carriers of the 677CC genotype. The highest level of Hcy was observed among MTHFR 677TT carriers with low B(12) intake (<2.0 microg/day), which resulted with a significant interaction (P=0.01). CONCLUSION: Vitamin B(12) is an important determinant of Hcy levels in Mexico. Supplementation of folic acid with vitamin B(12) may be preferable when the MTHFR 677T variant allele is prevalent.     

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.     

5,10-亚甲基四氢叶酸还原酶基因C677T位点突变与地方性砷中毒皮肤病变发生关系的研究

目的　 5 ,10- 亚甲基四氢叶酸还原酶 (MTHFR)是叶酸代谢关键酶 ,旨在了解该酶基因C6 77T位点突变是否是地方性砷中毒皮肤病变发生的遗传易感因素。方法　选择 5 0名出现砷性皮肤病变居民作为皮肤病变组 ,以同地区饮水砷浓度相近的 35名正常人作为对照 ,进行MTHFR基因C6 77T位点多态性分析(PCR- RFLP法 )、血清叶酸测定 (微生物法 )和维生素B1 2 测定 (电化学发光法 )。结果　皮肤病变组MTHFR基因C6 77T位点TT基因型占 34. 0 % ,T等位基因频率为 5 6 . 0 %。皮肤病变组和对照组基因型构成和等位基因频率差异无显著性。两组血清叶酸、VitB1 2 水平差异均无显著性。以血清叶酸水平≥ 10. 5nmol L且CC基因型作为参照 ,其它组粗OR值和经Logistic回归分析控制性别、年龄、水砷浓度、吸烟后的校正OR值均大于 1,但 95 %CI包含 1。结论　MTHFR基因C6 77T位点多态性与地方性砷中毒皮肤病变的发生无明显关联。     

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.     

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.     

Folate intake, serum homocysteine and methylenetetrahydrofolate reductase (MTHFR) C677T genotype are not associated with oral cancer risk in Puerto Rico

We examined the relationships between folate and methionine intake, serum homocysteine levels (as a biomarker for folate metabolism), and methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism genotype and risk of oral cancer in a population-based, case-control study in Puerto Rico. Structured questionnaires were used to collect information on demographic factors, usual adult diet, and tobacco and alcohol use. Oral epithelial cells and blood samples were collected from a subset of subjects. Analyses were conducted by logistic regression, adjusting for age, sex, lifetime smoking and lifetime alcohol intake, with the following numbers of cases/controls, respectively: dietary data (341/521); MTHFR genotype (148/149); and homocysteine (60/90). Although increased folate intake was associated with decreased oral cancer risk [adjusted odds ratio (OR) in highest vs. lowest quartile = 0.6, 95% confidence interval (CI): 0.4, 1.0, P(trend) = 0.05)], this finding was due almost entirely to folate intake from fruit (adjusted OR = 0.4, 95% CI: 0.2, 0.6; P(trend) = 0.0001), whereas other dietary folate sources showed no clear association. Methionine intake and serum homocysteine levels were not associated with oral cancer risk. Subjects with the MTHFR C677T homozygous variant (TT) genotype had a nonsignificantly lower risk, and risk patterns tended to differ by level of folate, methionine, alcohol intake and smoking, although the power to detect significant associations in subgroups of these variables was low. Risks for oral cancer are not folate specific; preventive recommendations for this disease should emphasize the importance of a healthy diet, including substantial intake of fruits.     

Methylenetetrahydrofolate reductase 677C-->T variant modulates folate status response to controlled folate intakes in young women

A common genetic variant in the methylenetetrahydrofolate reductase (MTHFR) gene involving a cytosine to thymidine (C-->T) transition at nucleotide 677 is associated with reduced enzyme activity, altered folate status and potentially higher folate requirements. The objectives of this study were to investigate the effect of the MTHFR 677 T allele on folate status variables in Mexican women (n = 43; 18-45 y) and to assess the adequacy of the 1998 folate U.S. Recommended Dietary Allowance (RDA), 400 micro g/d as dietary folate equivalents (DFE). Subjects (14 CC, 12 CT, 17 TT genotypes) consumed a low folate diet (135 micro g/d DFE) for 7 wk followed by repletion with 400 micro g/d DFE (7 CC, 6 CT, 9 TT) or 800 micro g/d DFE (7 CC, 6 CT, 8 TT) for 7 wk. Throughout repletion with 400 micro g/d DFE, the TT genotype had lower (P 0.05) in their response relative to the CC genotype. Throughout repletion with 800 micro g/d DFE, the CT genotype had lower (P 0.05) in the measured variables between the TT and CC genotypes. Repletion with 400 micro g/d DFE led to normal blood folate and desirable plasma tHcy concentrations, regardless of MTHFR C677T genotype. Collectively, these data demonstrate that the MTHFR C-->T variant modulates folate status response to controlled folate intakes and support the adequacy of the 1998 folate U.S. RDA for all three MTHFR C677T genotypes.     

新疆哈萨克族食管癌与叶酸摄入水平、亚甲基四氢叶酸还原酶基因多态关系的研究

目的探讨新疆哈萨克族人群食管癌与叶酸摄人水平及与叶酸代谢相关基因亚甲基四氢叶酸还原酶（MTHER）基因多态的关系。方法采用1：2配比的病例对照研究方法，收集120例哈萨克族食管癌患者，按同性别、同民族、年龄相差≤5岁、同一个居住地区等选取对照240例；选用聚合酶链反应-限制性片段长度多态性（PCR-RFLP）方法检测MTHFR C677T基因型，采用条件logistic回归进行统计分析。结果叶酸摄入量与哈萨克族食管癌有关（X^2=7．868，υ=1，P〈0．01），其OR值为0．519（95％CI：0．329-0．821），叶酸摄入水平高是保护因素；病例组和对照组MTHFR C677T基因型分布，经统计学检验，差异有统计学意义（X^2=15．823，υ=1，P〈0．01）；MTHFR 677CT、TT基因型个体发生食管癌的危险性是CC基因型个体的2．613倍（95％CI：1．628-4．194）；交互作用提示：叶酸摄入充足，可降低携带MTHFR 677CT、TT基因型个体发生食管癌的危险性。多因素条件logistic回归分析显示：饮用河水或渠水、饮食不规律、辛辣饮食、暴饮暴食、粮食存放超过1年、有食管或胃病变史√MTHFR677位点发生C→T改变等是哈萨克族食管癌的危险因素，叶酸摄入水平高是保护因素。结论叶酸摄入缺乏是新疆哈萨克族食管癌的主要危险因素；MTHFR C677T多态是哈萨克族食管癌的易感因素。     

A comparison of the effect of advice to eat either '5-a-day' fruit and vegetables or folic acid-fortified foods on plasma folate and homocysteine

OBJECTIVE: To assess and compare the effects of natural folate (100 micro g) with those of folic acid from fortified sources (100 micro g/day) on plasma folate and homocysteine. DESIGN: Randomized controlled trial (parallel groups). SETTING: Men and women living in South Wales, UK. SUBJECTS: A total of 135 healthy individuals recruited from the local workforce and blood donor sessions. All subjects possessed the 'wild-type' CC genotype for C677T polymorphism in methylenetetrahydrofolate reductase (MTHFR). INTERVENTIONS: Subjects underwent one of the following dietary interventions for 4 months: (1) fortified diet-usual diet plus 100 microg/day folic acid from fortified foods; (2) natural folate diet-usual diet plus 100 microg/day folate from natural sources; (3) control-usual diet. RESULTS: The fortified group increased reported intake of folic acid from fortified foods compared to other groups (P<0.001) achieving an extra 98 microg/day (95% CI 88-108). The natural folate group increased reported intake of natural source folates compared with the other two groups (P<0.001), but achieved a mean increase of only 50 microg/day (95% CI 34-66). Plasma folate increased (P<0.01) by a similar amount in both intervention groups compared to controls (fortified group 2.97, 95% CI 0.8-5.1; natural group 2.76, 95% CI 0.6-4.9. Plasma homocysteine, vitamins B(6) and B(12) were not significantly changed. CONCLUSIONS: Subjects achieved increases in folate intake using fortified foods more easily than by folate-rich foods, however both sources increased plasma folate by a similar amount. These levels of intake were insufficient to reduce homocysteine concentrations in MTHFR CC homozygotes, but may be more effective in other genotypes.