Differences In Plasma Homocysteine Levels Research Articles

The impact of MTHFR 677 C/T genotypes on folate status markers: a meta-analysis of folic acid intervention studies.

Methylenetetrahydrofolate reductase (MTHFR) is a key folate pathway enzyme with the T variant of the MTHFR gene increasing the risk of low folate status, particularly coupled with low folate intake. As genetic variability of MTHFR influences folate status, it is important to ensure an adequate intake that overrides genetic effects but minimises any adverse effects. Our aim was to assess the influence of MTHFR genotype on folate status followed by response to supplementation. We performed a meta-analysis of ten folate intervention studies to assess the degree to which MTHFR C677T genotype influenced plasma homocysteine and serum folate levels as measures of folate status. We then examined response after supplementation at intake values up to the upper tolerable limit. The MTHFR 677TT genotype was associated with higher plasma homocysteine (2.7μmol/L, TT vs. CT/CC; 2.8μmol/L, TT vs. CC) and lower serum folate (2.5nmol/L, TT vs. CT/CC; 3.6nmol/L, TT vs. CC). In two studies, the TT groups had mean plasma Hcy>15μmol/L. Serum folate levels were >7nmol/L for all genotype groups. After supplementation of 400 up to 1670μg DFEs of folic acid or folic acid+fortified foods and/or natural food folates for a minimum of 4weeks, there were no significant differences in plasma homocysteine levels; however, individuals with the TT genotype had a lower serum folate response to supplementation (7.2nmol/L, TT vs. CT/CC; 8.7nmol/L, TT vs. CC). This meta-analysis confirms observations from observational and intervention studies that MTHFR TT genotype is associated with increased plasma homocysteine and lowered serum folate and less response to short-term supplementation. The results can be used for modelling and guiding personalised intake recommendations for the nutrient folate.

Clinical significance of determining plasma homocysteine: case-control study on arterial and venous thrombotic patients

AimTo determine the differences in plasma homocysteine levels between three MTHFR 677 genotype subgroups in patients with thrombosis and in controls, as well as between patients with thrombosis and controls with the same MTHFR 677 genotype.MethodsThis case-control study was conducted in Clinical Center of Vojvodina, Novi Sad, from June to December 2011. We included 65 patients with either arterial or venous thrombosis (mean age, 40.97 ± 11.38 years) and 65 controls with no history or clinical evidence of any thrombotic event (mean age, 41.23 ± 11.12 years). Patients and controls were age- and sex-matched.ResultsIn comparison with controls, thrombotic patients had significantly higher homocysteine levels (12.81 ± 4.94 µmol/L vs 9.82 ± 3.68 µmol/L; P < 0.001) and significantly higher incidence of hyperhomocysteinemia (55% vs 22%; P < 0.001; odds ratio [OR] = 4.521). There were no significant differences in homocysteine levels between homozygous carriers, heterozygous carriers, and non-carriers of the MTHFR 677 mutation in either thrombotic patients (12.97 ± 5.40 µmol/L vs 12.55 ± 5.71 µmol/L vs 13.27 ± 1.71 µmol/L; P = 0.100) or controls (10.07 ± 2.50 µmol/L vs 10.25 ± 4.84 µmol/L vs 9.20 ± 2.44 µmol/L; P = 0.651). However, in comparison with controls, homozygous carriers in thrombotic patient group did not have significantly higher levels of homocysteine (12.97 ± 5.40 µmol/L vs 10.07 ± 2.50 µmol/L; P = 0.072), but heterozygous carriers (12.55 ± 5.71 µmol/L vs 10.25 ± 4.84 µmol/L; P = 0.020) and non-carriers (13.27 ± 1.71 µmol/L vs 9.20 ± 2.44 µmol/L; P < 0.001) did. There was no significant difference in homocysteine levels between patients with arterial and venous thrombosis (12.76 ± 3.60 µmol/L vs 12.86 ± 5.51 µmol/L; P = 0.990) and between patients with one thrombotic event and those with recurrent thrombotic events (12.14 ± 3.20 µmol/L vs 15.25 ± 8.51 µmol/L; P = 0.254).ConclusionPlasma homocysteine levels have a greater clinical significance in the prevention of thrombosis and managing its complications than MTHFR 677 genotyping.

The role of methylenetetrahydrofolate reductase C677T polymorphism on the peripheral blood natural killer cell proportion in women with unexplained recurrent miscarriages

ObjectiveTo examine the association between methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism and hyperhomocysteinemia in women with unexplained recurrent miscarriages (RM) and to investigate the association between MTHFR genotype variants and alloimmune activation, proportion of peripheral blood natural killer (pbNK) cells.MethodsA total of 39 patients with a history of two or more unexplained miscarriages were recruited to this study. The controls were women who had a live birth without a history of RM (n=50). The proportion of pbNK cells was measured by flow cytometry. Plasma homocysteine levels and the incidence of the MTHFR variant of the RM and control groups were compared. The proportion of pbNK cells was compared to the MTHFR variants in the RM group.ResultsNo differences were found between the two groups' mean plasma homocysteine levels (7.6±1.5 µmol/L vs. 7.1±2.1 µmol/L) or incidence of the MTHFR genotype variant (CC, 35% vs. 33%; CT, 40% vs. 53%; and TT, 25% vs. 14%). In the RM group, individuals with the TT variant (7.7±1.1 µmol/L) had higher homocysteine levels than those with the CC and CT variants (7.4±1.9 µmol/L and 7.4±1.2 µmol/L) and those with the CT variant (19.2±8.1%) had a higher proportion of CD3-/CD56+ pbNK cells than those with the CC and TT variants (17.7±6.6% and 17.9±7. 0%), but the results of both comparisons were statistically insignificant.ConclusionThese preliminary results show no difference in plasma homocysteine levels between the RM and control groups or among MTHFR genotype variants in the RM group, which may suggest that the plasma homocysteine level is difficult to use as a predictive marker of RM in the Korean population. A study of a larger number of patients is needed.

Testosterone regulation of renal cystathionine β-synthase: implications for sex-dependent differences in plasma homocysteine levels

Elevated plasma total homocysteine (tHcy) is an independent risk factor for ischemic heart disease and stroke. Epidemiological studies reveal that men have higher tHcy levels than women, but the mechanism underlying this sex-dependent difference is unknown. One route for intracellular disposal of homocysteine is catalyzed by cystathionine beta-synthase (CBS). Renal function is known to be an important determinant of tHcy, and, in this study, we demonstrate that renal CBS expression and activity in mice diminished approximately twofold after castration, whereas ovariectomization was without effect. The higher renal CBS activity in males (22.7 +/- 3.1 mmol cystathionine.h(-1).kg kidney(-1)) vs. females (8.4 +/- 3.4 mmol cystathionine.h(-1).kg kidney(-1), P < or = 10(-6)) in C57Bl/6J mice was associated with lower plasma tHcy levels in males vs. females, and this difference was exacerbated in Cbs+/- mice (7.7 +/- 1.9 micromol/l in males vs. 13.8 +/- 6.4 micromol/l in females, P = 0.005). Surprisingly, mammals exhibit a diversity of regulatory patterns for kidney CBS, with females exhibiting lower CBS activity in mice, higher in rats and humans, and being indistinguishable from males in rabbit, hamster, and guinea pig. Our data suggest that testosterone-dependent regulation of human CBS in kidney may contribute to sex-dependent differences in homocysteine transsulfuration.

677TT polymorphism of methylenetetrahydrofolate reductase in combination with low serum vitamin B12 is associated with coronary in‐stent restenosis

Recent studies have shown that a common mutation (nucleotide 677 C-->T) in the methylenetetrahydrofolate reductase (MTHFR) gene may contribute to a mild rise in plasma homocysteine levels and increase the incidence of coronary artery disease. Therefore, this study was designed to further investigate whether the effects of MTHFR 677 C to T mutation, plasma homocysteine, serum vitamin B12, and folate can influence restenosis after successful coronary stenting. We investigated 260 patients each with a lesion after successful coronary stent placement. All patients received a repeated angiography after 6 months, or earlier if clinically indicated. Angiographic in-stent restenosis (ISR) was defined as >or=50% diameter stenosis at follow-up. Genotyping for MTHFR was based on a polymerase chain reaction technique. Also fasting plasma homocysteine, vitamin B12, and folate levels were measured at the same time. The ISR rate was higher among the patients with the TT genotype than in those with the non-TT genotypes (64.0% versus 32.9%, P=0.002). There was no significant difference in plasma homocysteine levels among patients with the TT genotype and patients with the non-TT genotypes (15.9+/-7.6 versus 15.5+/-6.6 micromol/L, P=0.75). However, among the patients with the TT genotype, those with higher plasma homocysteine levels (>or=12 micromol/L) demonstrated a significantly higher ISR rate (75.0% versus 33.5%, P=0.001). Logistic regression analysis revealed that the combined presence of the MTHFR TT genotype and lower than average serum vitamin B12 (>or=550 pg/mL) resulted in the most significant difference in the risk of ISR (OR=3.57, CI=1.51-8.46, P=0.004; OR=2.36, CI=1.35-4.15, P=0.003). MTHFR 677TT polymorphism and low serum vitamin B12 each individually increased the risk of coronary ISR. Furthermore, the combination of these parameters resulted in a greater increase in risk.

Elevated plasma homocysteine levels in patients with isolated coronary artery ectasia

Coronary artery ectasia is a variant of coronary atherosclerosis. Hyperhomocysteinemia has emerged as a major, independent risk factor for cardiovascular diseases. The purposes of this study were to determine plasma hyperhomocysteine levels in patients with coronary artery ectasia, and to compare patients with coronary artery ectasia, coronary artery disease, and controls with normal coronary angiogram. The study population included 37 patients with coronary artery ectasia and 36 patients with coronary artery disease. The control group consisted of 32 patients with angiographically proven normal coronary arteries. Plasma hyperhomocysteine levels were measured in all study patients with an enzyme-linked immunosorbent assay. Plasma homocysteine levels were significantly higher in patients with both coronary artery ectasia and coronary artery disease than in the controls (14.8+/-1.1 and 15.9+/-0.8 vs. 2.5+/-0.6 micromol/l; P<0.001 and P<0.001, respectively). No significant differences in plasma homocysteine levels were found among CAE and CAD groups (P>0.05). We have demonstrated that patients with coronary artery ectasia and coronary artery disease have increased plasma hyperhomocysteine levels compared with the controls. These findings suggest that hyperhomocysteinemia may play an important role in the pathogenesis of coronary artery ectasia as in coronary artery disease.

Differences in plasma homocysteine levels between Zucker fatty and Zucker diabetic fatty rats following 3 weeks oral administration of organic vanadium compounds

Purpose: Recently, our laboratory group has reported that rats with Type 1 diabetes have decreased plasma homocysteine and cysteine levels compared to non-diabetic controls and that organic vanadium treatment increased plasma homocysteine concentrations to non-diabetic concentrations. However, to date, no studies have been done investigating the effects of organic vanadium compounds on plasma homocysteine and its metabolites in Type 2 diabetic animal model. These studies examined the effect of organic vanadium compounds [bis(maltolato)oxovanadium(IV) and bis(ethylmaltolato)oxovanadium(IV); BMOV and BEOV] administered orally on plasma concentrations of homocysteine and its metabolites (cysteine and cysteinylglycine) in lean, Zucker fatty (ZF) and Zucker diabetic fatty (ZDF) rats. ZF rats are a model of pre-diabetic Type 2 diabetes characterized by hyperinsulinemia and normoglycemia. The ZDF rat is a model of Type 2 diabetes characterized by relative hypoinsulinemia and hyperglycemia. Methods: Zucker lean and ZF rats received BMOV in the drinking water at a dose of 0.19±0.02 mmol/kg/day. Lean and ZDF rats received BEOV by oral gavage daily at dose of 0.1 mmol/kg. The treatment period for both studies was 21 days. At termination, animals were fasted overnight (∼16 h) and blood samples were collected by cardiac puncture for determination of plasma glucose, insulin and homocysteine levels. Plasma homocysteine and its metabolites levels were determined using high-pressure liquid chromatography. Plasma glucose was determined using a Glucose Analyzer 2. Plasma insulin levels were determined by radioimmunoassay. Plasma triglycerides were determined by an enzymatic assay methodology. Results: ZF ( n = 4 ) and ZDF ( n = 1 0 ) rats had significantly lower plasma homocysteine as compared to their respective lean groups (ZF 0.78±0.1 μmol/L vs. Zucker lean 2.19±0.7 μmol/L; ZDF 1.71±0.2 μmol/L vs. Zucker lean 3.02±0.3 μmol/L; p < 0.0 5 ). BMOV treatment in ZF rats restored plasma homocysteine levels to those observed in lean untreated rats (ZF treated: 2.04±0.2 μmol/L; lean 2.19±0.7 μmol/L). There was a modest effect of BMOV treatment on plasma glucose levels in ZF rats. BEOV treatment significantly decreased the elevated plasma glucose levels in the ZDF rats (lean 7.9±0.1 mmol/L; lean+vanadium 7.7±0.2 mmol/L; ZDF 29.9±0.4 mmol/L; ZDF+vanadium 17.4±0.3 mmol/L, p < 0.0 5 ). Organic vanadium treatment reduced cysteine levels in both ZF and ZDF rats. No differences in total plasma cysteinylglycine concentrations were observed. Conclusion: Plasma homocysteine levels are significantly reduced in a pre-diabetic model of Type 2 diabetes, which was restored to lean levels upon vanadium treatment; however, this restoration of plasma homocysteine levels was not seen in ZDF Type 2 diabetic rats following vanadium treatment. In the latter case vanadium treatment may not have totally overcome the insulin resistance seen in these animals.

Plasma Homocysteine Levels in Noninsulin-dependent Diabetes Mellitus with Retinopathy and Neovascular Glaucoma

This study was designed to evaluate plasma homocysteine levels in noninsulin-dependent diabetes mellitus patients (NIDDM) with preproliferative retinopathy and neovascular glaucoma. The experimental goal was to determine the relationship between plasma homocysteine content and the development of microvascular lesions. Plasma homocysteine levels were assessed in three experimental groups consisting of healthy controls (n = 30), NIDDM patients with preproliferative retinopathy (n = 20) and NIDDM patients with neovascular glaucoma (n = 20). Homocysteine levels were determined via a fluorescence polarization immunoassay method by an Abbot IMX instrument. Plasma homocysteine levels in NIDDM patients with preproliferative retinopathy and neovascular glaucoma (n = 40) were found to be significantly higher than those of controls (n = 30) (p < 0.01). When statistical analysis was performed separately among the three experimental groups, no significant difference in plasma homocysteine levels were found in patients with preproliferative retinopathy compared to controls. However, homocysteine levels in patients with neovascular glaucoma were found to be significantly higher than the control group (p < 0.001). No significant difference in plasma homocysteine levels could be detected between patients with preproliferative retinopathy and neovascular glaucoma. Hyperhomocysteinemia is a risk factor for the development of microvascular lesions in patients with NIDDM but cannot be used as a marker to assess the progression of lesions observed in neovascular glaucoma.

Possible ethnic differences in plasma homocysteine levels associated with coronary artery disease between south Asian and east Asian immigrants.

Hyperhomocysteinemia has been identified as a risk factor for coronary artery disease (CAD). South Asians appear to have a high incidence of CAD, while East Asians have a very low incidence. The present study was undertaken because the relative association of plasma homocysteine levels (PH) with CAD in South Asians (SA = Indian, Pakistani, Sri Lankan) and East Asians (EA = Chinese, Japanese) is not known. Fasting PH were drawn on all patients with CAD of SA (age 62.4+/-1.1 years, 72 men, 14 women) and EA (age 61.8+/-3.0 years, 13 men, 4 women) descent. These were compared with PH available from Caucasian (CA) patients (age 61.1+/-1.1 years, 89 men, 17 women) with CAD. The PH in SA, EA, and CA patients were 11.0+/-0.5, 7.6+/-0.5, and 10.8+/-0.6 micromol/l, respectively (p<0.001 between EA and SA/CA). Percentages of SA, EA, and CA with elevated PH (> 12.0 micromol/l) were 33.7, 5.9, and 28.2%, respectively. There were no significant differences in the lipid subfractions between the SA and EA group. History of smoking was significantly higher in the EA (52.9 vs. 26.2%), while hypertension and diabetes mellitus had similar prevalences. Significant differences in PH of SA versus EA patients with CAD exist. The relative contribution of homocysteine in the development of CAD appears to be less in EA immigrants. In contrast, the association between CAD and PH in SA immigrants appears to be similar to that of Caucasians.

Genetic defects as important factors for moderate hyperhomocysteinemia.

The genes for the enzymes methylenetetrahydrofolate reductase (MTHFR), methionine synthase (MS), methionine synthase reductase (MSR) and cytathionine-beta-synthase (CBS) play an important role in homocysteine metabolism. Rare mutations in these genes cause severe hyperhomocysteinemia and clinical symptoms. Growing interest has focused on common mutations with moderate effects on homocysteine levels. We studied 280 subjects of different age groups for the following mutations: MTHFR677C-->T and 1298A-->C, MS2756A-->G, MSR66A-->G and the 68 bp insertion in the CBS gene. The median value for homocysteine increased significantly with age (median homocysteine levels: 7.5, 12.4 and 16.5 micromol/l in the age groups 20-43, 65-75 and 85-96 years, respectively). The genotypes of the MTHFR677C-->T mutation were associated with differences in plasma homocysteine levels, but without reaching significance. Individuals homozygous for the MTHFR677C-->T mutation had a 2.3 micromol/l higher median homocysteine level compared to individuals with the wild-type allele. This effect was pronounced in combination with low folate levels and abolished with higher folate in plasma. For the other three mutations no association with homocysteine values could be determined. The analysis of homocysteine metabolite cystathionine by backward regression analysis revealed a significant correlation of the MS2756A-->G mutation with cystathionine level. This increase could indicate a disturbed remethylation. In summary, larger and homogeneous study populations are necessary to quantify the small effects of common mutations on homocysteine levels. This may also be the reason that no effects of genetic interactions between two genotypes were observed.

Plasma homocysteine levels in patients with deep venous thrombosis.

Increased risk of arterial and venous thromboembolic disease is well documented in the homocystinuric patient. There is growing evidence that hyperhomocysteinemia is an independent risk factor for premature arteriosclerotic disease, including cerebral, peripheral, and coronary vascular diseases. So far no association has been established between hyperhomocysteinemia and venous thromboembolism. We studied 35 patients, young adults (age less than 56 years) with venographically and/or ultrasonographically verified deep venous thrombosis (DVT). Patients with coexisting diseases were excluded. Plasmahomocysteine levels before and after intake of methionine were measured 3 months or more after the time of diagnosis and compared with 39 control subjects. We found no significant difference in plasmahomocysteine levels between the young adults with deep venous thrombosis and control subjects. This indicates that hyperhomocysteinemia is not a frequent cause of DVT.

Lack of association between plasma homocysteine levels and microangiopathy in type 1 diabetes mellitus.

The reactive vascular-injuring amino acid homocysteine was previously shown to be increased in plasma in diabetic patients with clinical signs of nephropathy. In this study, plasma homocysteine was measured in type 1 diabetic patients with normoalbuminuria (n = 22), microalbuminuria (n = 40) and proteinuria (n = 14) in order to investigate whether plasma homocysteine levels are increased already at the stage of incipient nephropathy, i.e. microalbuminuria. Furthermore, patients were characterized according to the degree of retinopathy. Plasma homocysteine in the whole population (n = 76) was related to B-Folate (r = 0.38, p < 0.01), S-Creatinine (r = 0.55, p < 0.001), S-Urea (r = 0.37, p < 0.01), U-Albumin (r = 0.46, p < 0.001), urinary N-acetyl-beta- glucosaminidase (r = 0.40, p < 0.001), systolic blood pressure (r = 0.36, p < 0.01) and diabetes duration (r = 0.44, p < 0.001). There were no differences in plasma homocysteine levels between patients with normoalbuminuria (8.0 +/- 1.7 mumol l-1; mean +/- SD) and those with microalbuminuria (9.1 +/- 3.4 mumol l-1). However, patients with clinical signs of nephropathy had higher plasma homocysteine levels (12.9 +/- 5.7 mumol l-1, p < 0.01) compared to the other two groups. There was no association between plasma homocysteine levels and different degrees of retinopathy. Thus, the present study does not show any relation between plasma homocysteine levels and early stages of diabetic nephropathy or retinopathy indicating that elevated concentrations of plasma homocysteine does not explain the increased risk for atherosclerosis observed in patients with microalbuminuria.