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.     

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.     

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.     

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.     

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.     

Effect of interaction between adherence to a Mediterranean diet and the methylenetetrahydrofolate reductase 677C-->T mutation on homocysteine concentrations in healthy adults: the ATTICA Study

BACKGROUND: Dietary and genetic factors may influence the effect of raised homocysteine concentrations on coronary artery disease risk. OBJECTIVE: We evaluated the effect of the interaction between adoption of a Mediterranean diet and the methylenetetrahydrofolate reductase gene (MTHFR) 677C-->T mutation on homocysteine concentrations in healthy adults participating in the ATTICA study. DESIGN: We studied demographic, lifestyle, clinical, biochemical, and genetic information from 322 men (x +/- SD age: 46 +/- 13 y) and 252 women (45 +/- 14 y) who had no clinical evidence of cardiovascular or any other chronic disease. We also measured total plasma homocysteine concentrations, the distribution of the MTHFR genotype, and adherence to a Mediterranean diet. RESULTS: The distribution of MTHFR genotypes was as follows: homozygous normal (CC), 41%; heterozygous (CT), 48%; and homozygous mutant (TT), 11%. Homocysteine concentrations were higher in persons with the TT genotype than in those with the CC and CT genotypes (x +/- SD: 15.8 +/- 9 compared with 11.3 +/- 8 and 10.8 +/- 9 micromol/L, respectively; P < 0.001). The Mediterranean diet score was not significantly associated with homocysteine concentrations (P = 0.89). However, after control for potential confounders, the stratified analysis showed that adherence to a Mediterranean diet was associated with reduced homocysteine concentrations in persons with the TT and CT genotypes (beta = -0.21, P = 0.002, and beta = -0.14, P = 0.025, respectively) but not in those with the CC genotype (beta = -0.03, P = 0.38). CONCLUSION: The observed association of an MTHFR 677C-->T gene-diet interaction on homocysteine concentrations may provide a pathophysiologic explanation for how a Mediterranean diet may influence coronary risk in persons with raised homocysteine concentrations.     

同型半胱氨酸代谢异常与原发性高血压的病例对照研究

目的 探讨同型半胱氨酸代谢异常与原发性高血压的关系。方法 从上海市一个社区中随机选取１２７例３５～７５岁的原发性高血压病人和１７０例正常血压者。使用高效液相色谱结合电化学方法检测血清中同型半胱氨酸总浓度,使用放射免疫法同时测定血清中叶酸和Ｂ１２浓度。采用聚合酶链反应－限制性片段长度多态性分析亚甲基四氢叶酸还原酶（ＭＴＨＦＲ）基因多态性。结果 调整年龄和性别后,病例和对照组同型半胱氨酸水平分别为１０     

B-group vitamins, MTHFR C677T polymorphism and carotid intima-media thickness in clinically healthy subjects

OBJECTIVE: Plasma B-group vitamins and age may affect the carotid intima-media thickness (IMT) in subjects with different 677TT genotype of the methylenetetrahydrofolate reductase (MTHFR) gene. DESIGN: A hospital-based cross-study. SETTING: Genomic and Vascular Center, Changhua Christian Hospital, Changhua, Taiwan. SUBJECTS: Five hundred and forty-one clinically healthy subjects. INTERVENTION: Fasting plasma, homocysteine (Hcy), vitamin B(6), vitamin B(12), folate and B-mode carotid ultrasound. RESULTS: MTHFR genotype, plasma concentrations of folate, vitamin B(6) and vitamin B(12) and age were significantly correlated to the plasma Hcy concentration. MTHFR 677TT carriers had higher concentrations of Hcy than did subjects with the CC and CT genotypes. Age, sex, body mass index and plasma Hcy were independent contributors to increase carotid IMT. However, with stratification by mean value of age and B-group vitamins concentrations, we found that at advanced age, lower plasma folate and vitamin B(12) were three risk factors involved in the enhancing effect of the MTHFR 677TT genotype on the increase of plasma Hcy and carotid IMT. CONCLUSION: MTHFR 677TT-related carotid atherosclerosis was only identified in healthy elderly subjects with lower level of plasma folate and vitamin B(12). SPONSORSHIP: Changhua Christian Hospital.     

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.     

妊高征患者亚甲基四氢叶酸还原酶基因多态的检测

目的　探讨妊高征患者亚甲基四氢叶酸还原酶 (MTHFR)基因C6 77T多态与血浆同型半胱氨酸 (Homo cysteine ,Hcy)、叶酸及维生素B12 水平的关系。方法　采用 (PCR -RFLPCPR -restrictionfragmentlengthpolymdor phism)法对 82例妊高征患者 (Hcy血症组和无Hcy血症组 )及 90例正常孕妇 (对照组 )进行MTHFR基因C6 77T等位基因检测 ,并同时测量孕妇血浆中的同型半胱氨酸、叶酸和维生素B12 水平。结果　妊高征组A(Hcy血症组 )纯合变异型T6 77/T6 77频率 (0 34)显著高于妊高征组B(无Hcy血症组 ) (0 11,P <0 0 1)和正常对照组 (0 13,P <0 0 1) ;各组中随 6 77T等位基因数量的增加 ,血浆Hcy水平也增加 ,但是对叶酸和维生素B12 水平没有明显影响。结论　MTH FR基因C6 77T多态可以导致妊高征孕妇血液中同型半胱氨水平升高 ,MTHFR基因C6 77T多态是妊高征发病的遗传危险因素之一     

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.     

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.     

Homocysteine synthesis is elevated but total remethylation is unchanged by the methylenetetrahydrofolate reductase 677C->T polymorphism and by dietary folate restriction in young women

The effects of folate status and the methylenetetrahydrofolate reductase (MTHFR) 677C-->T polymorphism on the kinetics of homocysteine metabolism are unclear. We measured the effects of dietary folate restriction on the kinetics of homocysteine remethylation and synthesis in healthy women (20-30 y old) with the MTHFR 677 C/C or T/T genotypes (n = 9/genotype) using i.v. primed, constant infusions of [(13)C(5)]methionine, [3-(13)C]serine, and [(2)H(3)]leucine before and after 7 wk of dietary folate restriction (115 mug dietary folate equivalents/d). Dietary folate restriction significantly reduced folate status ( approximately 65% reduction in serum folate) in both genotypes. Total remethylation flux was not affected by dietary folate restriction, the MTHFR 677C-->T polymorphism, or their combination. However, the percentage of remethylation from serine was reduced approximately 15% (P = 0.031) by folate restriction in C/C subjects. Further, homocysteine synthesis rates of T/T subjects and folate-restricted C/C subjects were twice that of C/C subjects at baseline. In conclusion, elevated homocysteine synthesis is a cause of mild hyperhomocysteinemia in women with marginal folate status, particularly those with the MTHFR 677 T/T 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.     

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.     

MTHFR variants reduce the risk of G:C->A:T transition mutations within the p53 tumor suppressor gene in colon tumors

5,10-Methylene-tetrahydrofolate reductase (MTHFR) is a key enzyme in folate-mediated 1-carbon metabolism. Reduced MTHFR activity has been associated with genomic DNA hypomethylation. Methylated cytosines at CpG sites are easily mutated and have been implicated in G:C-->A:T transitions in the p53 tumor suppressor gene. We investigated 2 polymorphisms in the MTHFR gene (C677T and A1298C) and their associations with colon tumor characteristics, including acquired mutations in Ki-ras and p53 genes and microsatellite instability (MSI). The study population comprised 1248 colon cancer cases and 1972 controls, who participated in a population-based case-control study and had been analyzed previously for MSI, acquired mutations in Ki-ras, p53, and germline MTHFR polymorphisms. Multivariable-adjusted odds ratios are presented. Overall, MTHFR genotypes were not associated with MSI status or the presence of any p53 or Ki-ras mutation. Individuals with homozygous variant MTHFR genotypes had a significantly reduced risk of G:C-->A:T transition mutations within the p53 gene, yet, as hypothesized, only at CpG-associated sites [677TT vs. 677CC (referent group) OR = 0.4 (95% CI: 0.1-0.8) for CpG-associated sites; OR = 1.5 (0.7-3.6) for non-CpG associated sites]. Genotypes conferring reduced MTHFR activity were associated with a decreased risk of acquired G:C-->A:T mutations within the p53 gene occurring at CpG sites. Consistent with evidence on the phenotypic effect of the MTHFR C677T variant, we hypothesize that this relation may be explained by modestly reduced genomic DNA methylation, resulting in a lower probability of spontaneous deamination of methylated cytosine to thymidine. These results suggest a novel mechanism by which MTHFR polymorphisms can affect the risk of colon cancer.     

Different allele-distribution of mthfr 677 C -> T and mthfr -393 C -> a in patients classified according to subtypes of Lesch's typology

AIMS: The typology by Lesch distinguishes between four subtypes: type 1 (model of allergy), type 2 (model of anxiety or conflict), type 3 (alcohol as an antidepressant), and type 4 (alcohol as adaptation). Taking into account that alcohol dependence is associated with elevated homocysteine levels, this study was undertaken to investigate different MTHFR (methylenetetrahydrofolate reductase) genotypes related to homocysteine metabolism in patients with alcohol dependence who were classified according to Lesch's typology (LT). Subjects and methods: 134 non-abstinent chronic alcoholics (112 males, 22 females; mean age 44.2 (SD 8.9) years) were classified according to LT and divided into four groups: LT 1 (n = 26), LT 2 (n = 65), LT 3 (n = 58), and LT 4 (n = 18). Total plasma homocysteine levels and MTHFR genotypes -393, 677, and 1,793 were determined. RESULTS: We observed a significantly higher frequency of the thermolabile MTHFR 677 C-->T variant (TT) in patients classified as subtype LT4 when compared with subtypes LT2 and LT3 (P = 0.005). Furthermore, for the MTHFR -393 C --> A-polymorphism, significantly more AC/AA variants were found in subtype LT4 (P = 0.034). No differences in allele-distribution were detected for MTHFR 1793. CONCLUSION: To our knowledge, this is the first study evaluating MTHFR genotypes in patients who were classified according to LT. Significantly different distributions of MTHFR 677 and -393 variants within Lesch Type 4 as compared with Types 2 and 3 hint at genetic determination of Lesch subtypes.     

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.     

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.     

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.