Methylenetetrahydrofolate Reductase C677T Mutation Research Articles

Abstracts of literature

Abstracts of literature

Role of a common mutation in the homocysteine regulatory enzyme methylenetetrahydrofolate reductase in ischemic stroke.

A common mutation in methylenetetrahydrofolate reductase (MTHFR), a homocysteine metabolic pathway enzyme, has been associated with increased homocysteine levels and increased risk for premature cardiovascular disease. The purpose of this study was to assess the association between the prevalence of the MTHFR mutation, hyperhomocysteinemia, and subtypes of ischemic stroke in an elderly population comprised of three age-balanced groups of patients. The presence of the C677T MTHFR mutation was determined by a direct polymerase chain reaction-based assay performed on blood samples from 136 patients with acute ischemic stroke, 95 patients with atherosclerotic risk factors for stroke (including some with a history of previous stroke or transient ischemic attack), and 52 healthy control subjects. The prevalence of the homozygous C677T mutation was not significantly higher in the elderly stroke patients (7%) than in the atherosclerotic risk (8%) or healthy elderly control (2%) groups. Plasma homocysteine levels were higher in the acute stroke patient group (14.5+/-4.5 micromol/L) and atherosclerotic risk patient group (14.6+/-6.2 micromol/L) compared with the control subjects (10.3+/-3.1 micromol/ L, P < 0.03). Homozygotes for the C677T MTHFR mutation did not have significantly higher homocysteine levels than non-homozygotes. Moderate hyperhomocysteinemia, though common in older patients with ischemic cerebrovascular disease, is not attributable, at least in this patient group, to a higher prevalence of the C677T MTHFR mutation.

Prevalence of Prothrombin G20210A, Factor V G1691A (Leiden), and Methylenetetrahydrofolate Reductase (MTHFR) C677T in Seven Different Populations Determined by Multiplex Allele-specific PCR

Individuals belonging to six racial groups (African American, Asian Indian, Caucasian, Hispanic, Korean, Native American), and a seventh group comprised of referred patients with thrombosis were genotyped for the prothrombin G20210A mutation, the factor V G1691A (Leiden) mutation, and the methylenetetrahydrofolate reductase (MTHFR) C677T mutation by multiplexed allele-specific PCR. The prothrombin 20210A and factor V 1691A allele frequencies in the thrombosis patients, 3.2% and 9.5%, were significantly higher than those in the random Caucasians, 1.3% and 1.8%, (p = 0.043 and p <0.001, respectively). The relative risk of venous thrombosis was determined to be 2.4-fold for carriers of the prothrombin 20210A allele (odds ratio = 2.54; 95% confidence interval = 0.94, 6.82) and 4.5-fold for carriers of the factor V 1691A allele (odds ratio = 5.06; 95% confidence interval = 2.25, 11.36). Among the seven populations, significant differences were observed in the MTHFR 677T allele distribution, however this mutation was not determined to be a risk factor for venous thrombosis in the patient group studied, either alone or in combination with the prothrombin 20210A and/or the factor V 1691A allele(s).

Inherited DNA mutations contributing to thrombotic complications in patients with Sickle cell disease

Thrombosis may play an important role in the pathophysiology of certain complications of sickle cell disease (SCD), including stroke and avascular necrosis (AVN). Currently there is no laboratory or clinical parameter that can identify patients who are at highest risk of developing these thrombotic complications. We hypothesized that some patients with SCD have an inherited hypercoagulable state that results in an increased risk of developing stroke or AVN. We examined the role of two common inherited thrombophilic mutations that, in other populations, have been associated with arterial and venous thrombosis and are amenable to screening with DNA restriction enzyme analysis. The C677T mutation in the methylenetetrahydrofolate reductase (MTHFR) gene and the C1565T mutation in the platelet glycoprotein IIIa (GPIIIa) gene were evaluated. We analyzed genomic DNA from 86 children and adults with SCD, including 16 patients with a history of a clinical stroke and 14 patients with AVN, for the presence of these mutations. The C677T MTHFR mutation was found in 19% of patients with stroke, 14% of patients with AVN, and 14% of patients with neither complication (P = NS). The C1565T GPIIIa mutation was found in 25% of patients with stroke, 14% of patients with AVN, and 18% of patients with neither complication (P = NS). Although each of these mutations is relatively common in patients with SCD, neither is independently associated with an increased risk of developing stroke or AVN. Am. J. Hematol. 59:267–272, 1998. © 1998 Wiley-Liss, Inc.

Inherited DNA mutations contributing to thrombotic complications in patients with sickle cell disease.

Thrombosis may play an important role in the pathophysiology of certain complications of sickle cell disease (SCD), including stroke and avascular necrosis (AVN). Currently there is no laboratory or clinical parameter that can identify patients who are at highest risk of developing these thrombotic complications. We hypothesized that some patients with SCD have an inherited hypercoagulable state that results in an increased risk of developing stroke or AVN. We examined the role of two common inherited thrombophilic mutations that, in other populations, have been associated with arterial and venous thrombosis and are amenable to screening with DNA restriction enzyme analysis. The C677T mutation in the methylenetetrahydrofolate reductase (MTHFR) gene and the C1565T mutation in the platelet glycoprotein IIIa (GPIIIa) gene were evaluated. We analyzed genomic DNA from 86 children and adults with SCD, including 16 patients with a history of a clinical stroke and 14 patients with AVN, for the presence of these mutations. The C677T MTHFR mutation was found in 19% of patients with stroke, 14% of patients with AVN, and 14% of patients with neither complication (P = NS). The C1565T GPIIIa mutation was found in 25% of patients with stroke, 14% of patients with AVN, and 18% of patients with neither complication (P = NS). Although each of these mutations is relatively common in patients with SCD, neither is independently associated with an increased risk of developing stroke or AVN.

Opposite effects of plasma homocysteine and the methylenetetrahydrofolate reductase C677T mutation on carotid artery geometry in asymptomatic adults.

Studies of symptomatic patients have identified hyperhomocysteinemia as an independent risk factor for vascular disease. In case-control studies, a point mutation (C677T) in the gene encoding 5,10-methylenetetrahydrofolate reductase (MTHFR) has also been linked to an increased risk of vascular disease through its effect on homocysteinemia. Our aim was to extend these observations to asymptomatic subjects by studying the influence of both homocysteinemia and its mutation on carotid artery geometry. We examined 144 subjects free of atherosclerotic lesions. Fasting homocysteinemia was measured by high-performance liquid chromatography with fluorometric detection. MTHFR genotype was analyzed by polymerase chain reaction followed by HinfI digestion. Carotid artery geometry was characterized by internal diameter and intima-media thickness, as assessed by a high-resolution echo-tracking system. Subjects in the upper homocysteine tertile had a greater carotid internal diameter than did subjects in the middle and lower tertiles (6516+/-770 versus 6206+/-641 and 5985+/-558 microm, respectively; P<0.001). Subjects homozygous for the mutation had a smaller carotid artery internal diameter than did subjects heterozygous or homozygous for the wild-type allele (5846+/-785 versus 6345+/-673 and 6199+/-671 microm, respectively; P<0.05). Homocysteinemia was not significantly increased in subjects homozygous for the mutation. In multivariate regression analysis, homocysteinemia was independently and positively associated with lumen diameter (P=0.0008) and wall thickness (P=0.020). Conversely, homozygosity for the mutation was negatively associated with internal diameter (P=0.009). These preliminary data suggest that mildly elevated homocysteinemia and homozygosity for the MTHFR C677T mutation are associated with opposite preclinical modifications of carotid artery geometry. If confirmed, these results may have important implications for new treatment strategies for vascular disease before the onset of clinical manifestations.

Genetic susceptibility to pregnancy-related venous thromboembolism: Roles of factor V Leiden, prothrombin G20210A, and methylenetetrahydrofolate reductase C677T mutations

Objective: This study’s objective was to evaluate the association between venous thromboembolism during pregnancy and the postpartum period and the factor V Arg 506 Gln (factor V Leiden), the prothrombin G20210A, and methylenetetrahydrofolate reductase C677T polymorphisms. Study Design: In this case-control study 42 case patients and 213 control subjects (parous age-matched women without history of thrombosis) were genotyped for all the polymorphisms. Moreover, antiphospholipid antibodies and protein C, protein S, and antithrombin III deficiencies were investigated in each case. Results: Ten case patients (23.8%) and 4 control subjects (1.9%; odds ratio 16.3, 95% confidence interval 4.8-54.9) carried the factor V Leiden mutation; 13 case patients (31.0%) and 9 control subjects (4.2%; odds ratio 10.2, 95% confidence interval 4.0-25.9) were carriers of the prothrombin G20210A allele. Finally, 12 case patients (28.6%) and 34 control subjects (16.0%; odds ratio 2.1, 95% confidence interval 1.0-4.5) were homozygotes for methylenetetrahydrofolate reductase C677T. Overall, mutations were found in 25 case patients (59.5%) and 47 control patients (22.2%; odds ratio 5.2, 95% confidence interval 4.9-19.6). One patient carried the antithrombin III deficiency and 1 the protein S deficiency, whereas 2 women had a primary antiphospholipid syndrome. Conclusions: The significant risk estimates of having a pregnancy-related venous thromboembolism in the presence of the prothrombotic genetic risk factors analyzed suggest to screen for these mutations women with a personal history of thromboembolic events during pregnancy or the postpartum period. (Am J Obstet Gynecol 1998;179:1324-8.)

B vitamins and homocysteine in cardiovascular disease and aging.

The sulfur-containing amino acid, homocysteine, is formed from the essential amino acid methionine, and a number of B vitamins are involved in methionine metabolism. Pyridoxine, vitamin B6, is a cofactor for cystathionine beta synthase, which mediates the transformation of homocysteine to cystathionine, the initial step in the transsulfuration pathway and the urinary excretion of sulfur. In a normal diet there is conservation of the carbon skeleton, and about 50% of the homocysteine formed is remethylated to methionine via steps that require folic acid and vitamin B12. A deficiency of any of these three vitamins leads to modest homocyst(e)ine elevation, as does diminished renal function, both of which are common in the elderly. It is also established that homocyst(e)ine elevation of this order is associated with increased cardiovascular risk but is also associated with most established risk factors, although it is thought to be an independent contributor. In the inborn error of metabolism homocystinuria due to cystathionine beta synthase deficiency there is greatly increased circulating homocyst(e)ine and a clear association with precocious vascular disease. In about 50% of these patients there is a vascular event before the age of 30 years. The homocysteine-induced adverse vascular changes appear to result from endothelial and smooth muscle cell effects and increased thrombogenesis. We have documented a highly significant reduction in the occurrence of vascular events during 539 patient years of treatment in 32 patients with cystathionine beta synthase deficiency (mean age 30 years, range 9-66 years) by aggressive homocyst(e)ine lowering with pyridoxine, folic acid, and B12 (p = 0.0001). The 15 pyridoxine nonresponsive patients also received oral betaine. Although a cause and effect relationship is postulated for the increased cardiovascular risk associated with mild homocysteine elevation, a common cause of this elevation is the methylenetetrahydrofolate reductase C677T mutation. Homozygotes occur in about 11% of Caucasian populations. However, the mutation is not associated with increased coronary risk. Since mild homocysteine elevation is easily normalized by B vitamin supplementation, usually with folic acid, it remains for controlled clinical trials of this inexpensive therapy to determine whether normalizing mild homocyst(e)ine elevation reduces cardiovascular risk.

Methylenetetrahydrofolate Reductase C677T Mutation, Plasma Homocysteine, and Folate in Subjects From Northern Italy With or Without Angiographically Documented Severe Coronary Atherosclerotic Disease: Evidence for an Important Genetic-Environmental Interaction

Moderate elevation of plasma total homocysteine (tHcy) is a strong and independent risk factor for coronary artery disease (CAD). It can result from genetic or nutrient-related disturbances in the transsulfuration or remethylation pathways for Hcy metabolism. A point mutation (C677T; Ala-to-Val) in the gene encoding the 5,10-methylenetetrahydrofolate reductase (MTHFR) has been recently reported to render the enzyme thermolabile and less active. Studies on the role of this mutation as a risk factor for CAD have given conflicting results. We studied a total of 415 subjects, 278 with angiographically documented multivessel CAD and 137 with angiographically documented normal coronary arteries. The overall frequency of the MTHFR V/V homozygous genotype was 15.7% (with 52.5% heterozygous and 31.8% normal). Subgroup analysis showed no significant differences between CAD and CAD-free subjects. A genotype/phenotype correlation study showed a marked effect of folate on the association between MTHFR genotypes and tHcy. Among individuals with folate levels below the median (11.5 nmol/L), fasting tHcy was significantly increased not only in V/V homozygotes (by 59%) but also, at intermediate values, in A/V heterozygotes (by 21% on average). Conversely, the mutation resulted neutral with respect to tHcy levels in subjects with adequate folate levels. We conclude that, in our population, the MTHFR C677T mutation is rather common, but it does not appear to be associated per se to CAD. A genetic-environmental interaction may contribute to the vascular risk by elevating tHcy when folate status is low.

Methylenetetrahydrofolate Reductase C677T Mutation, Plasma Homocysteine, and Folate in Subjects From Northern Italy With or Without Angiographically Documented Severe Coronary Atherosclerotic Disease: Evidence for an Important Genetic-Environmental Interaction

AbstractModerate elevation of plasma total homocysteine (tHcy) is a strong and independent risk factor for coronary artery disease (CAD). It can result from genetic or nutrient-related disturbances in the transsulfuration or remethylation pathways for Hcy metabolism. A point mutation (C677T; Ala-to-Val) in the gene encoding the 5,10-methylenetetrahydrofolate reductase (MTHFR) has been recently reported to render the enzyme thermolabile and less active. Studies on the role of this mutation as a risk factor for CAD have given conflicting results. We studied a total of 415 subjects, 278 with angiographically documented multivessel CAD and 137 with angiographically documented normal coronary arteries. The overall frequency of the MTHFR V/V homozygous genotype was 15.7% (with 52.5% heterozygous and 31.8% normal). Subgroup analysis showed no significant differences between CAD and CAD-free subjects. A genotype/phenotype correlation study showed a marked effect of folate on the association between MTHFR genotypes and tHcy. Among individuals with folate levels below the median (11.5 nmol/L), fasting tHcy was significantly increased not only in V/V homozygotes (by 59%) but also, at intermediate values, in A/V heterozygotes (by 21% on average). Conversely, the mutation resulted neutral with respect to tHcy levels in subjects with adequate folate levels. We conclude that, in our population, the MTHFR C677T mutation is rather common, but it does not appear to be associated per se to CAD. A genetic-environmental interaction may contribute to the vascular risk by elevating tHcy when folate status is low.

Prevalence of Factor V Leiden and Methylenetetrahydrofolate Reductase C677T Mutations in Azerbaijan

Prevalence of Factor V Leiden and Methylenetetrahydrofolate Reductase C677T Mutations in Azerbaijan -

Homocysteine, 5,10-méthylénetétrahydrofolate reductase et thrombose veineuse profonde. Enquête auprès de 120 patients en médecine interne

In the last few years, the association of deep vein thrombosis with frequent biological risk factors and genetic polymorphisms has significantly modified the field of venous thrombosis. In this study, we measured plasma homocysteine levels and tested the C677T methylenetetrahydrofolate reductase (MTHFR) mutation. Plasma homocysteine levels and test for C677T MTHFR mutation were performed in 120 consecutive patients with objectively diagnosed deep vein thrombosis, and in 120 controls. We found a strong association between hyperhomocysteinemia and thrombosis (odd ratio: 2.43 IC 95% [1.27-4.7]). Conversely the C677T MTHFR gene polymorphism is only associated with hyperhomocysteinemia but not associated with thrombosis. This is a preliminary study to the ongoing international multicentric study of SNFMI (Société nationale française de m0+edecine interne) concerning hyperhomocysteinemia and venous thrombosis.

Screening of the C677T mutation on the methylenetetrahydrofolate reductase gene in French patients with neural tube defects.

We report the analysis of the distribution of the C677T mutation on the methylenetetrahydrofolate reductase (MTHFR) gene in prenatally diagnosed neural tube defects (NTD) cases and controls. In contrast to previous reports, we found the same distribution in fetuses with NTD and controls, which suggests that the MTHFR C677T mutation cannot be regarded as a genetic risk factor for NTD.

A common mutation in the methylenetetrahydrofolate reductase gene (C677T) increases the risk for deep-vein thrombosis in patients with mutant factor V (factor V:Q506).

Hyperhomocysteinemia is a frequent risk factor for deep-vein thrombosis. A common mutation (C677T) in the gene encoding for methylenetetrahydrofolate reductase (MTHFR) is responsible, in the homozygous state, for decreased enzyme activity and mild hyperhomocysteinemia and is associated with increased risk for cardiovascular disease. We studied the prevalence of C677T MTHFR in 77 patients with deep-vein thrombosis and in 154 age- and sex-matched healthy control subjects. In the same individuals, we also evaluated the frequency of the coexistence of C677T MTHFR with mutant factor V:Q506, a common risk factor for deep-vein thrombosis. Sixteen patients (20.8%) and 35 control subjects (22.7%) were homozygous for the C677T MTHFR mutation (odds ratio [OR] = 0.8, 95% confidence interval [CI] = 0.4-2.0). Sixteen patients (20.8%) and 4 control subjects (2.6%) had factor V:Q506; of them, 10 patients and 3 control subjects had isolated factor V:Q506 (adjusted OR = 6.3, 95% CI = 1.6-25.3) and 6 patients and 1 control subject also had C677T MTHFR (adjusted OR = 17.3, 95% CI = 2.0-152.9). The OR for the coexistence of the two mutations was 65% to 75% higher than the expected joint effect calculated by either an additive (OR = 6.0) or multiplicative (OR = 4.4) model. The homozygous C677T mutation of MTHFR per se is not a risk factor for deep-vein thrombosis but increases the risk associated with factor V:Q506. Due to the high prevalence of C677T MTHFR, it is likely that previous studies, which did not look for this mutation, overestimated the relative risk of thrombosis associated with factor V:Q506 alone.

Factor V Leiden and Thermolabile Methylenetetrahydrofolate Reductase in Extreme Old Age

Both factor V Leiden and the C677T methylenetetrahydrofolate reductase (MTHFR) gene mutation are associated with premature vascular disease, and yet are found at surprisingly high allele frequencies in European populations, 2.7% and 35% respectively. We have investigated the prevalence of these mutations in 87 UK residents over the age of ninety, to look for any evidence of their association with premature death. Five factor V Leiden heterozygotes were found, giving an allele frequency of 2.9%, similar to that in the general UK population. The frequency of the thermolabile C677T MTHFR mutation was 36% with 11% homozygotes, again similar to that in the UK population; these genotypes are in Hardy-Weinberg equilibrium, suggesting that there is not strong selection against the homozygous state. One person was both heterozygous for factor V Leiden and homozygous for the C677T mutation. This study suggests that neither factor V Leiden nor thermolabile MTHFR are risk factors for premature death.

PULMONARY EMBOLISM AND PREMATURE LABOR IN A PATIENT WITH BOTH FACTOR V LEIDEN MUTATION AND METHYLENETETRAHYDROFOLATE REDUCTASE GENE C677T MUTATION

Multiple risk factors for thrombosis were found in a 21 year old female who experienced three episodes of premature labor and developed severe pulmonary embolism during her third pregnancy. This patient is heterozygous for factor V Leiden mutation and homozygous for methylenetetrahydrofolate reductase (MTHFR) gene nucleotide 677 C to T (C677T) point mutation. This is a first report of the concordance of homozygous MTHFR C677T mutation in an individual with factor V Leiden mutation. This new case provides further evidence that synergism of multiple genetic and acquired risk factors is often encountered in young patients with symptomatic venous thrombosis.