Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:1.5.7.1 (methylenetetrahydrofolate reductase)
2,116 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Limited data are available on the determinants of homocysteinemia or the association between plasma homocysteine (Hcy) levels and prevalent cardiovascular disease (CVD) in maintenance dialysis patients. We assessed etiology of renal failure, residual renal function and dialysis adequacy-related variables, and vitamin status, as determinants of fasting total plasma homocysteine (Hcy) in 75 maintenance dialysis patients. We also assessed the potential interactive effect on plasma Hcy of folate status and a common mutation (ala to val; homozygous val-val frequency approximately 10%) in methylenetetrahydrofolate reductase (MTHFR), a folate-dependent enzyme crucial for the remethylation of homocysteine (Hcy) to methionine. Lastly, we evaluated whether the Hcy levels differed amongst these patients in the presence or absence of prevalent CVD, after adjustment for the traditional CVD risk factors. Fasting total plasma Hcy, folate, pyridoxal 5'-phosphate (PLP; active B6), B12, creatinine, glucose, total and HDL cholesterol levels, and presence of the ala to val MTHFR mutation were determined, and clinical CVD and CVD risk factor prevalence were ascertained. General linear modelling/analysis of covariance revealed: (1) folate status and serum creatinine were the only significant independent predictors of fasting Hcy; (2) there was a significant interaction between presence of the val mutation and folate status, i.e., among patients with plasma folate below the median (< 29.2 ng/ml), geometric mean Hcy levels were 33% greater (29.0 vs. 21.8 microM, P = 0.012) in the pooled homozygotes (val-val) and heterozygotes (ala-val) for the ala to val mutation, vs. normals (ala-ala); (3) there was no association between prevalent CVD and plasma Hcy. Given potentially intractable survivorship effects, prospective cohort studies will be required to clarify the relationship between plasma Hcy or any putative CVD risk factor, and incident CVD in dialysis patients. If a positive association between plasma Hcy and incident CVD can be established in maintenance dialysis patients, the current data provide a rationale for additional folic acid supplementation in this patient population.
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PMID:Folate status is the major determinant of fasting total plasma homocysteine levels in maintenance dialysis patients. 878 50

Elevated concentration of plasma total homocysteine (tHcy) is a common risk factor for arterial occlusive diseases. Folic acid (FA) supplementation usually lowers tHcy levels, but initial tHcy and vitamin levels, multivitamin use, and polymorphisms in the gene for 5, 10-methylenetetrahydrofolate reductase (MTHFR) may contribute to variability in reduction. We tested the effects of a 3-week daily intake of 1 or 2 mg of FA supplements on tHcy levels in patients with and without coronary heart disease (CHD) who were analyzed for the C677T MTHFR mutation. Prior multivitamin intake and baseline vitamin and tHcy levels were also compared with responsiveness to folate supplementation. Both dosages of FA lowered tHcy levels similarly, regardless of sex, age, CHD status, body mass index, smoking, or plasma creatinine concentration. In non-multivitamin users, FA supplements reduced tHcy by 7% in C/C homozygotes and by 13% or 21% in subjects with one or two copies of the T677 allele, respectively; the corresponding reductions were smaller in users of multivitamins. Moreover, T/T homozygotes had elevated tHcy and increased susceptibility to high levels of tHcy at marginally low plasma folate levels, as well as enhanced response to the tHcy-lowering effects of FA. Although other factors are probably involved in the responsiveness of tHcy levels to FA supplementation, about one third of heterogeneity in responsiveness was attributable to baseline tHcy and folate levels and to multivitamin use.
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PMID:The effects of folic acid supplementation on plasma total homocysteine are modulated by multivitamin use and methylenetetrahydrofolate reductase genotypes. 919 68

Hyperhomocysteinemia is frequent in hemodialysis patients and represents an independent risk factor for vascular disease in these patients. Elevated total homocysteine (tHcy) plasma levels can results from defective remethylation of Hcy to methionine due to decreased activity of the enzyme methylenetetrahydrofolate reductase (MTHFR). A genetic aberration in the MTHFR gene (677 C to T substitution) has been shown to result in reduced MTHFR activity. We tested the hypothesis that elevation of tHcy plasma levels in hemodialysis patients is influenced by the 677 C to T mutation of the MTHFR gene and examined the relation of the genotype with tHcy, folate and vitamin B12 plasma levels in these patients. The allelic frequency of the MTHFR mutation was evaluated in 203 patients maintained on chronic hemodialysis treatment. Total Hcy, folate, vitamin B12 levels and the MTHFR mutation were analyzed in 69 of the 203 patients and in 69 age- and sex-matched healthy control subjects. The allelic frequency of the 677 C to T transition in the MTHFR gene in hemodialysis patients was 34.7% versus 35.5% in healthy controls. Of 203 patients 26 (12.8%) were homozygous for the mutation (+/+) versus 10.2% in healthy subjects. The heterozygous (+/-) genotype was identified in 43.8% of patients versus 50.7% in controls. The mean tHcy level in hemodialysis patients was 28.7 +/- 11.0 mumol/liter versus 10.0 +/- 3.0 mumol/liter in control subjects. The mean tHcy levels were 36.4 +/- 13.4 mumol/liter in (+/+) patients and 12.2 +/- 4.5 mumol/liter in (+/+) controls, 28.7 +/- 10.8 mumol/liter in (+/-) patients and 9.9 +/- 2.7 mumol/liter in (+/-) controls and 25.4 +/- 8.5 mumol/liter in (-/-) hemodialysis patients versus 9.7 +/- 2.8 mumol/liter in (-/-) controls: There was no significant difference of folate and vitamin B12 concentrations in patients and controls with different MTHFR genotypes. Analysis of covariance including age, gender, folate concentrations, vitamin B12 levels, albumin and creatinine as covariables revealed a significant influence of the (+/+) genotype, albumin and folate status on tHcy levels in hemodialysis patients. Together, our data demonstrate that the extent of hyperhomocysteinemia in hemodialysis patients is not only the result of uremia or folate status, but is also genetically determined by the (+/+) MTHFR genotype. The presence of the 677 C to T mutation in the MTHFR gene does not appear to represent a risk factor for development of end-stage renal disease.
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PMID:Mutation (677 C to T) in the methylenetetrahydrofolate reductase gene aggravates hyperhomocysteinemia in hemodialysis patients. 926 11

It was the aim of this study to determine the associations of clinical and laboratory data with plasma homocyst(e)ine levels in patients with transient ischemic attack (TIA) or minor stroke (MS), with special reference to their 677C to T mutation status in the 5,10-methylenetetrahydrofolate reductase (5,10-MTHFR) gene. Seventy-six patients with TIA or MS were investigated at least 3 months after their (last) clinical event. By means of univariate analysis, significant correlations of homocyst(e)ine levels with male gender (P<0.02), age (P<0.0005), creatinine levels (P<0.0002), folate levels (inversely, P<0.05), and alcohol use (P<0.02) were found, but not with vitamin B12 levels. Multivariate regression analysis, including age, creatinine levels, and folate levels as independent variables, revealed age (P<0.01) and creatinine levels (P<0.02) to be significantly correlated with homocyst(e)ine levels. After adjustment for age, creatinine levels and homocyst(e)ine levels remained significantly correlated to each other (P<0.005), whereas the relation between folate levels and homocyst(e)ine levels was no longer significant (P=0.10). Mutation-positive patients exhibited moderately and statistically non-significantly higher homocyst(e)ine levels than mutation-negative patients, particularly those who were homozygous positive. Homocyst(e)ine levels were closely correlated with creatinine levels (P<0.0002) and with folate levels (inversely, P<0.05), but only in mutation-positive and not in mutation-negative patients. Homozygous positive, heterozygous positive, and mutation-negative patients did not differ with respect to clinical and laboratory data concerning 'risk factors for stroke' or co-existing vascular disease. In conclusion, the associations of creatinine levels and, inversely, of folate levels with plasma homocyst(e)ine levels in patients with TIA or MS are dependent on the 5,10-MTHFR mutation status. Significant correlations between these variables were found only in mutation-positive but not in mutation-negative patients.
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PMID:677C to T mutation in the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene and plasma homocyst(e)ine levels in patients with TIA or minor stroke. 956 60

The mechanisms leading to elevated total homocysteine concentrations in peritoneal dialysis patients are only partially understood. We show that a common polymorphism in the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene (C677T transition) results in increased total homocysteine levels in peritoneal dialysis patients compared to age- and sex-matched healthy individuals. The allelic frequency of the C677T transition in the MTHFR gene in peritoneal dialysis patients (0.29) was comparable to the frequency in healthy individuals (0.34). Separate comparison of the total homocysteine plasma levels between non-carriers of the MTHFR polymorphism (C/C), heterozygous (C/T) and homozygous (T/T) subjects was performed by analysis of covariance in the patient and the control group. In the patient group the mean total homocysteine level was 61.7 +/- 40.1 mumol/liter in individuals with the (T/T) genotype, which was significantly higher than the total homocysteine concentration of 23.1 +/- 15.8 mumol/liter in (C/T) patients and 22.2 +/- 11.1 mumol/liter for non-carriers (P = 0.0001). Vitamin B12 (P = 0.0001), folate (P = 0.0005), serum creatinine (P = 0.016), albumin (P = 0.0157) and dialysis center (P = 0.0173) significantly influenced total homocysteine plasma levels in peritoneal dialysis patients, whereas this was not the case for age, gender, weekly Kt/V, weekly creatinine clearance, residual renal function, duration of dialysis, mode of peritoneal dialysis and vitamin intake. Folate levels in peritoneal dialysis patients were significantly affected by the MTHFR genotype (P = 0.016). Elevated total homocysteine levels in diabetic patients with cardiovascular disease were associated with increased cardiovascular morbidity. In summary, the present study provides evidence that homozygosity for the C677T transition in the MTHFR gene, low vitamin B12 and low folate levels result in elevated total homocysteine levels in peritoneal dialysis patients.
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PMID:Major determinants of hyperhomocysteinemia in peritoneal dialysis patients. 960 12

Elevated plasma total homocysteine (tHcy) levels, either measured in the fasting state or after oral methionine loading, are associated with an increased risk of atherothrombotic disease. Fasting and post-methionine hyperhomocysteinemia (HHC) overlap to a limited extent; both can occur as familial traits. We investigated determinants of fasting, postmethionine and delta (ie, post-methionine minus fasting levels) tHcy levels in 510 subjects of 192 HHC-prone families including 161 patients with clinical vascular disease and 349 without vascular disease. We focused on tHcy levels in relation to levels of vitamin B12, B6 and folate and the methylenetetrahydrofolate reductase (MTHFR) C677T mutation. Multivariate linear analyses adjusted for the presence of vascular disease showed that fasting tHcy was significantly related to folate and vitamin B12, and the presence of the MTHFR TT genotype and the T allele, and to age, smoking habits, and serum levels of creatinine. Both post-methionine and delta tHcy levels were related to serum folate levels, and the presence of the MTHFR TT genotype and the T allele, and to postmenopausal status, and body mass index. An interaction was found between MTHFR TT genotype and serum folate levels for both fasting and post-methionine tHcy, ie, for a given decrease in serum folate, homocysteine levels increased more in subjects with the TT genotype than in those with the CC genotype. Fasting, post-methionine and delta tHcy were higher in patients with vascular disease than in their healthy siblings, but these levels were less dependent on serum folate levels (P<0.05), whereas the effect of MTHFR genotype was stronger (P=0.01). This study found evidence that post-methionine and delta tHcy levels are not only influenced by factors affecting homocysteine transsulfuration but also by factors that affect remethylation. The explained variances of fasting, post-methionine and delta tHcy were 49%, 62%, and 78%, respectively. We also found evidence, in patients with premature vascular disease but not in their healthy siblings, for a factor that increases tHcy levels but weakens the normal inverse relation between folate and tHcy and amplifies the effect of the MTHFR genotype.
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PMID:Determinants of fasting and post-methionine homocysteine levels in families predisposed to hyperhomocysteinemia and premature vascular disease. 1032 85

Moderately elevated plasma homocysteine levels have been established as an independent risk factor for atherosclerosis and its complications, including cerebrovascular disease. A common mutation (C677T) in the gene encoding for the enzyme methylenetetrahydrofolate reductase (MTHFR) has been linked to increased plasma homocysteine levels in homozygous carriers, particularly in the presence of low folate levels. However, the results of most of the previous studies suggest that the C677T MTHFR mutation is not a significant risk factor for arterial disease. This discrepancy might, at least partly, be due to the fact that plasma homocysteine levels are influenced by several other factors, including age, gender, renal function, and vitamin status. We investigated the relation between plasma homocysteine levels, the C677T MTHFR mutation, and these other factors in a population of 96 patients with transient ischemic attacks or minor strokes and in 96 age- and sex-matched healthy control subjects. We further tested the value of a multivariate model for the prediction of plasma homocysteine levels under particular consideration of the MTHFR mutation status. In the patients, plasma homocysteine levels were significantly higher than in the healthy control subjects. With regard to the MTHFR mutation, the distribution of the C/C, C/T, and T/T genotypes was not significantly different between patients and healthy control subjects. Univariate (linear regression) analysis revealed significant (positive) correlations between plasma homocysteine levels on the one hand and age and creatinine on the other, the latter particularly in subjects with creatinine levels in the upper quartile. Significant (negative) correlations were found between plasma homocysteine levels, vitamin B12, and folate levels. However, these relations could much better be expressed by means of a multiplicative regression model. T/T subjects exhibited slightly higher homocysteine levels than C/C and C/T subjects; however, the differences between the 3 genotypes were not significant. Multivariate (stepwise regression) analysis revealed age, vitamin B12 levels, folate levels, and creatinine levels as significant independent variables influencing plasma homocysteine levels, whereas the MTHFR mutation status and gender were removed from the model. Considering all 192 subjects, only 28.8% of the variance of plasma homocysteine levels could be accounted for by the model. However, in homozygous carriers of the MTHFR mutation, the predictive power of the model is very high, explaining 76.1% of the variance of plasma homocysteine levels. According to our results, the C677T mutation does not constitute a major risk factor for transient ischemic attack or minor stroke, even under consideration of other possibly confounding factors that are known to affect plasma homocysteine levels. However, it is possible to predict plasma homocysteine levels in homozygous carriers of the mutation with high accuracy. The knowledge of the MTHFR mutation status may therefore help to identify subjects at high risk for hyperhomocysteinemia.
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PMID:Genetic and nongenetic factors influencing plasma homocysteine levels in patients with ischemic cerebrovascular disease and in healthy control subjects. 1036 Jun 32

Moderate hyperhomocysteinemia is an atherogenic risk factor and plays an important role in geriatrics. Here, we have investigated the role of hyperhomocysteinemia in two elderly groups: 104 longeval subjects of 85-102 years, 100 seniors aged 65-75 years, and 75 controls of 19-60 years. Elevated homocysteine levels were found in 58% of longeval subjects in comparison with 32% in seniors. The homocysteine level in serum correlated positively with age as well as serum creatinine, and inversely with serum folate, but there was no correlation with serum B-vitamins. The frequency of vitamin B deficiency in serum of longeval subjects compared to seniors was as follows: vitamin B6 43% vs. 22%, vitamin B12 20% vs. 8%, and folic acid 1% in both groups. Increased serum creatinine levels (> 1.1 mg/dl) were found in 63% of the longeval subjects and in 32% of seniors. The 677-missense mutation in the methylenetetrahydrofolate reductase (MTHFR) gene, responsible for moderate homocysteine elevation, was found in 35, 37 and 27% of alleles in longeval persons, senior subjects and younger controls, respectively, showing no significant difference in frequency distributions of the MTHFR gene mutation. It can be concluded that hyperhomocysteinemia is very common with increased age. Its importance as an atherogenic risk factor with advanced age has to be clarified.
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PMID:Hyperhomocysteinemia in high-aged subjects: relation of B-vitamins, folic acid, renal function and the methylenetetrahydrofolate reductase mutation. 1038 Dec 82

The effect of 5,10-methylenetetrahydrofolate reductase (MTHFR) 677C-->T and 1298A-->C on total homocysteine (tHcy), folate and vitamin B(12) levels was investigated in 733 kidney graft recipients. The six major genotype combinations were used as grouping variables, and age, gender, BMI, serum creatinine, and creatinine clearance and ln-folate, ln-vitamin B(12), or logarithmus naturalis tHcy (ln-tHcy) were used as covariates in three ANCOVA and multiple stepwise linear regression models. Hyperhomocysteinemia was present in 49.7% of the patients. The allele frequency of MTHFR 677T and 1298C was 0.319 and 0.326. MTHFR genotype and all other variables were significant predictors of ln-tHcy (higher tHcy plasma levels for MTHFR 677TT/1298AA versus all other five genotype groups: P < 0. 05). BMI, creatinine clearance, ln-tHcy, and MTHFR genotype influenced ln-folate (lower folate levels for MTHFR 677TT/1298AA versus all other genotype groups: P < 0.05). Creatinine clearance and ln-tHcy were the only predictors of ln-vitamin B(12) levels. In a prespecified subgroup analysis (n = 496), the MTHFR genotype also influenced tHcy levels and compound heterozygous patients had significantly lower folate levels as compared with MTHFR 677CC/1298AA and 677CC/1298CC. This study shows that the MTHFR 677TT/1298AA and 677CT/1298AC genotypes are significant predictors of tHcy and folate plasma levels.
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PMID:Effect of MTHFR 1298A-->C and MTHFR 677C-->T genotypes on total homocysteine, folate, and vitamin B(12) plasma concentrations in kdiney graft recipients. 1100 24

Hyperhomocyst(e)inemia is a known risk factor for the development of atherosclerotic vascular damage. Plasma homocyst(e)ine levels are influenced by nutritional and hereditary factors. A point mutation (cytosine to thymidine substitution; C677T) in the gene encoding 5,10-methylenetetrahydrofolate reductase (MTHFR) makes the enzyme thermolabile and has been associated with elevated homocyst(e)ine levels in homozygous carriers (TT genotypes). We evaluated the relationship between the T allele encoding for the thermolabile variant of MTHFR and several biochemical risk factors and early signs of hypertensive and atherosclerotic organ damage in 206 untreated patients with primary hypertension. The MTHFR genotype was evaluated by polymerase chain reaction. Albuminuria was measured as albumin-to-creatinine ratio in three nonconsecutive first morning urine samples (negative urine culture). Persistent Mi (Alb+) was defined as an average albumin-to-creatinine ratio between 2.38 and 19 (men) and 2.96 and 20 (women). Left ventricular (LV) mass index (LVMI) was assessed by M-B mode echocardiography (LV hypertrophy, LVH = LVMI > or = 125 g/m2), carotid geometry by high-resolution ultrasound scan, and retinal vascular changes by direct ophthalmoscopy (Keith-Wagener classification). The prevalence of Mi, LVH, and retinopathy was 14%, 45%, and 42%, respectively. The prevalence of carotid plaque was 25%. Allele frequencies for C (wild-type allele) and T allele (mutant allele) were 56% and 44%, respectively. Genotype frequencies were CC 29%, CT 54%, TT 17% according to Hardy Weinberg equilibrium. There were no differences as for age, sex, body mass index, blood pressure levels, lipid profile, smoking habits, and alcohol intake, and LVMI and urinary albumin excretion on the basis of MTHFR genotype. Patients with TT polymorphism showed a higher prevalence of retinal vascular changes (TT, 61% v CT + CC, 38%; P < .02) and carotid plaque (TT, 42% v CT + CC, 21%; P < .05) compared to patients with CC and CT polymorphism. Moreover, patients with T allele showed increased carotid artery size as demonstrated by intima plus media thickness (IT, 0.79 +/- 0.05 mm v CT + CC, 0.67 +/- 0.02 mm; P < .02), relative wall thickness (TT, 0.23 +/- 0.01 mm v CT + CC, 0.20 +/- 0.005 mm; P < .02), and surface area (TT, 19 +/- 1.9 mm2 v CT + CC, 15 +/- 0.55 mm2; P < .05). Multiple linear regression analysis demonstrated that MTHFR genotype and systolic blood pressure independently influence intima-media thickness and together account for about 11% of its variations (r2 = 0.11, F = 9.7, dF = 1-205, P < .0001). Homozygosity for the T allele of the MTHFR gene is an independent risk factor for the development of early atherosclerotic organ damage in hypertensive patients.
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PMID:5,10-Methylenetetrahydrofolate reductase polymorphism and early organ damage in primary hypertension. 1133 84


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