Biological and clinical implications of the MTHFR C677T polymorphism (original) (raw)
Related papers
2003
Background: Methylenetetrahydrofolate reductase (MTHFR) is one of the main regulatory enzymes of homocysteine metabolism. Elevated plasma total homocysteine (tHcy) is a major risk for cardiovascular disease. A common 677C£T mutation in the MTHFR gene results in decreased enzymic activity, and contributes to increased plasma tHcy, in association with low plasma folate. A recently described 1298A£C mutation in the MTHFR gene clearly reduces MTHFR activity (although to a lesser extent than the 677C£T) but its effect on plasma tHcy levels is not yet clear. Aim: To investigate the frequency of these two MTHFR polymorphisms in a Portuguese population, and to correlate the MTHFR genotype with the biochemical phenotype at the level of homocysteine and folate concentrations. Design: Prospective population survey.
Journal of Pediatric Gastroenterology and Nutrition, 2005
In the present study, the determinants of fasting plasma homocysteine in diabetic subjects were examined; whether plasma homocysteine and vascular disease are related and the influence of the C677T polymorphism in the methylenetetrahydrofolate reductase (MTHFR) gene on serum and erythrocyte folate, plasma homocysteine and vascular disease. Diabetic clinic subjects (Type I, n l 354; Type II, n l 392) were recalled for a cross-sectional survey. Standard methods were used to measure biochemical variables and to characterize vascular disease and MTHFR genotype. Plasma homocysteine was significantly and directly related to age, male sex and serum urea, and inversely related to serum folate and vitamin B12, independently in stepwise regression. When corrected for age and sex, homocysteine was significantly related to hard end points of coronary artery disease and stroke (each P 0.01), remaining significant when additionally adjusted for serum folate (P l 0.043 and P l 0.019 respectively). Serum folate was not clearly related to these events, although there was a trend to associate with the lower quintile of serum folate. The MTHFR genotype was not a determinant of plasma homocysteine, even in those in the lowest quintile of serum folate, nor of vascular disease. TT homozygosity at residue 677 was associated with elevation of total erythrocyte folate compared with both other genotypes (P 0.0001), almost certainly due to the diversion of 5,10-methylenetetrahydrofolate into derivates subsequent to the partial metabolic block that results from the MTHFR enzyme defect. In conclusion, in this clinic cohort of people with diabetes, vascular disease is related to plasma homocysteine, which is correlated with serum folate. The MTHFR genotype does not significantly influence either plasma homocysteine or vascular disease, despite it being a determinant of erythrocyte folate, which reflects its effect on folate metabolism.
Journal of Molecular Medicine, 2001
Molecular defects in genes encoding enzymes involved in homocysteine metabolism may account for mild hyperhomocysteinemia, an independent and graded risk factor for cardiovascular disease (CVD). We examined the relationship of two polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) gene, the 677C→T and 1298A→C variants, to MTHFR activity, homocysteine concentrations, and risk of CVD in a population of 190 vascular disease patients and 601 apparently healthy controls. The mean specific and residual MTHFR activities were significantly lower in 677CT and 677TT individuals (both P<0.001). The 1298A→C mutation alone showed no effect on MTHFR activities. However, when the 677C→T genotype was taken into account, the 1298A→C mutation also caused a significant decrease in MTHFR activities, which was observed in both the homozygous 1298CC (P<0.001) and the heterozygous 1298AC states (P=0.005). Both the 677TT as the 677CT genotypes were associated with significantly higher fasting and postload homocysteine levels than 677CC (P<0.001 and P=0.003, respectively). The 1298A→C mutation had no effect on fasting or postload homocysteine levels. Since homocysteine itself is considered to be positively associated with the risk of CVD, these findings indicate that the 1298A→C mutation cannot be considered a major risk factor for CVD.
Atherosclerosis, 1997
Homozygosity lor a 677C-+T mutation at the locus that codes for 5,10-methylenetetrahydrofolate reductase (MTHFR), a folate-dependent crucial enzyme in homocysteine metabolism, may render the enzyme thermolabile and less active and has been associated with increased levels of plasma total homocysteine (tHcy). We assessed whether this mutation was associated with increased risk of coronary atherosclerosis and plasma levels of tHcy and furthermore studied whether folate status would modify the associations. Data were collected from subjects with substantial coronary atherosclerosis (;>90% occlusion in one and £: 40% occlusion in a second coronary artery, referred to as cases, it = 131) or virtually no coronary narrowing (referred to as coronary controls, n = 87) and from a population-based control group (n ~ 100), all residing in the Rotterdam area. The Netherlands. Both males and females, aged 25-65 years were studied. The frequency of homozygosity for the mutation (+ / +) in cases (10.0%) di not significantly differ statistically from that observed in coronary controls (11.5%, P = 0.71), population-based controls (7.0%, /? = 0.43), or combined control groups (9.1%, P « 0.80). In the overall group (as well as in the three subgroups), plasma tf-Icy levels, fasting and to a lesser extent after a methionine-loading test, were higher in + / + subjects than in homozygous normal /-), whereas heterozygous subjects (+ /-) had intermediate levels (P trend 'V B 0.001). The + / + erythrocyte folate levels <790 nmol/1 (population median) had a 77% (95% Cl, 27-144%) higher geometric mean fasting tHcy (21.4, /¿mol/1) than those with higher erythrocyte folate (12. j /¿mol/1). The odds ratio (OR) of coronary atherosclerosis for + / + subjects, with + / and I subjects as the reference group, in analyses with combined control groups, was 1.1 (95% Cl, 0.5-2.4). The ORs were 2.2 (95% Cl, 0.7 6.8) and 0.6 (95% Cl, 0.2 1.7) among subjects with low and high folate levels, respectively. Our study indicates that homozygosity lor the 677C-*■ T MTHFR mutation, especially in combination with low folate status, predisposes to high plasma levels of fasting tHcy. However, homozygosity for this mutation, whether or mil in combination with low folate status, was not associated with increased risk of coronary artery disease.
MTHFR 677TT genotype and disease risk: is there a modulating role for B-vitamins?
Proceedings of the Nutrition Society, 2014
Methylenetetrahydrofolate reductase (MTHFR) is a critical folate-metabolising enzyme which requires riboflavin as its co-factor. A common polymorphism (677C→T) in the MTHFR gene results in reduced MTHFR activity in vivo which in turn leads to impaired folate metabolism and elevated homocysteine concentrations. Homozygosity for this polymorphism (TT genotype) is associated with an increased risk of a number of conditions including heart disease and stroke, but there is considerable variability in the extent of excess risk in various reports. The present review will explore the evidence which supports a role for this polymorphism as a risk factor for a number of adverse health outcomes, and the potential modulating roles for B-vitamins in alleviating disease risk. The evidence is convincing in the case which links this polymorphism with hypertension and hypertensive disorders of pregnancy, particularly preeclampsia. Furthermore, elevated blood pressure was found to be highly responsiv...
Circulation, 1996
Background Hyperhomocysteinemia appears to be an independent risk factor for coronary disease. Elevated levels of plasma total homocysteine (tHCY) can result from genetic or nutrientrelated disturbances in the transsulfuration or remethylation pathways for homocysteine metabolism. The enzyme 5,10-methylenetetrahydrofolate reductase (MTHFR) catalyzes the reduction of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, the predominant circulatory form of folate, which serves as a methyl donor for remethylation of homocysteine to methionine. A common mutation in MTHFR recently has been identified. Methods and Results We assessed the polymorphism in MTHFR, plasma tHCY, and folate using baseline blood levels among 293 Physicians' Health Study participants who developed myocardial infarction (MI) during up to 8 years of follow-up and 290 control subjects. The frequency of the three genotypes was (−/−) (homozygous normal), 47%; (+/−) (heterozygous), 41%; and (+/+) (homozygous mutant), 12%, with a similar distribution among both MI case patients and control subjects. Compared with those with genotype (−/−), the relative risk (RR) of MI among those with (+/−) was 1.1 (95% CI, 0.8 to 1.5), and it was 0.8 (0.5 to 1.4) for the (+/+) genotype; none of these RRs were statistically significant. However, those with genotype (+/+) had an increased mean tHCY level (mean±SEM, 12.6±0.5 nmol/mL), compared with those with genotype (−/−) (10.6±0.3) (P<.01). This difference was most marked among men with low folate levels (the lowest quartile distribution of the control subjects): those with genotype (+/+) had tHCY levels of 16.0±1.1 nmol/mL, compared with 12.3±0.6 nmol/mL (P<.001) for genotype (−/−). Conclusions In this population, MTHFR polymorphism was associated with higher homocysteine levels but not with risk of MI. A gene-environment interaction might increase the risk by elevating tHCY, especially when folate intake is low.
Journal of Cardiovascular Disease Research, 2011
Researchers have determined that Indians face a higher risk of heart disease, despite the fact that nearly half of them are vegetarians and lack many of the other traditional risk factors. In the below-30 age group, coronary artery disease mortality among Indians is three-fold higher than in the whites in United Kingdom and ten-fold higher than the Chinese in Singapore. High levels of homocysteine have been widely linked to the early onset of heart diseases in other populations, although a definite proof among Indians is lacking, which needs to be investigated by way of screening for factors responsible for high homocysteine levels. Objective: To screen for genetic factors responsible for hyperhomocysteinemia and the risk for premature coronary artery disease. Materials and Methods: A total of 100 individuals with proven premature coronary artery disease and 200 age-and-sex matched controls were screened for polymorphisms in Methylenetetrahydrofolate reductase (MTHFR) (C677T) Methionine synthase (MS) genes (A2756G, C2758G), and the B12 and Folate levels were estimated. Results: Results from the mutational analysis revealed that in the study group, seven individuals had a polymorphism for the C677T allele in the MTHFR gene (one homozygous and six heterozygous) (Fischer's Exact test P > 0.046) (OR: 0.2711 95% CI 0.0774 to 0.9491). Six were heterozygous for the A2756G polymorphism in the MS gene (Fischer's Exact test P > 0.0012). None showed a polymorphism at the C2758G allele in the MS gene. Four controls showed heterozygosity for the C677T polymorphism and none for the MS gene. The B12 and Folate levels were significantly lower in the study group as compared to the controls. Conclusions: It is important to know which factors determine the total homocysteine concentrations. In the general population, the most important modifiable determinants of tHcy are folate intake and coffee consumption. Smoking and alcohol consumption are also associated with the total homocysteine concentrations, but more research is necessary to elucidate whether these relations are not originating from residual confounding due to other lifestyle factors.
Human Genetics, 2007
Two functional single nucleotide polymorphisms, 677C > T and 1298A > C have been described for the methylenetetrahydrofolate (MTHFR) gene. Both are associated with reduced enzyme activity in vitro. For the 677T, but not the 1298C allele, signiWcantly lower serum folate and higher plasma total homocysteine (tHcy) have been reported. We genotyped 10,034 middle-aged (50-64 years old) subjects and measured serum folate and tHcy. Within strata of 677 genotypes, 1,298 genotypes had signiWcantly diVerent serum folate and tHcy (P · 0.03 for all comparisons). Each additional 1298C allele reduced mean serum folate and increased mean tHcy, by (on average) 4.5 and 3.0%, respectively. In comparison, within strata of 1,298 genotypes, the increase from no, to one 677Tallele reduced serum folate and increased tHcy by, 7.1 and 6.3%, respectively. Lowest serum folate and highest tHcy level was found for the 677TT/1298AA genotype. The diVerence in tHcy was signiWcantly larger at low folate than at high folate when genotypes 677TT/ 1298AA and 677CT/1298AA, 677CT/1298AC and 677CC/1298AC, and genotypes 677CT/1298AC and 677CT/1298AA were compared. We interpreted these data in the context of a model of the MTHFR enzyme that describes the enzyme as a dimer that mainly exist in six diVerent conWgurations. The model reconciled the observed phenotypic eVects of the 677/1,298 combination genotypes with previous in vitro measurements, and identiWed enzyme conWgurations that are sensitive to low folate levels. In conclusion, this report demonstrates functional inference of the MTHFR 677 C > T and 1,298 A > C polymorphisms from a large-scale epidemiological study.
International journal of molecular medicine, 2007
We studied 692 Swedish children and adolescents (aged 9-10 or 15-16 years, respectively), in order to evaluate the effect of the methylenetetrahydrofolate reductase (MTHFR) 677C>T, 1298A>C, and 1793G>A polymorphisms on total plasma homocysteine concentrations (tHcy). Genotyping was performed with Pyrosequencing™ technology. The MTHFR 677C>T polymorphism was associated with increased tHcy concentrations in both the children and the adolescents (P<0.001 for both age groups) in both genders. The effect of MTHFR 1298A>C was studied separately in subjects with the 677CC and 677CT genotypes, and the 1298C allele was found to be associated with higher tHcy levels both when children were stratified according to 677C>T genotypes, and when using haplotype analyses and diplotype reconstructions. The 1793A allele was in complete linkage disequilibrium with the 1298C allele. It was still possible to show that the 1793A allele was associated with lower tHcy levels, statistically significant in the adolescents. In conclusion, a haplotype-based approach was slightly superior in explaining the genetic interaction on tHcy plasma levels in children and adolescents than a simple genotype based approach (R 2 adj 0.44 vs. 0.40). The major genetic impact on tHcy concentrations is attributable to the MTHFR 677C>T polymorphism. The common 1298A>C polymorphism had a minor elevating effect on tHcy, whereas the 1793G>A polymorphism had a lowering effect on tHcy.