Higher Homocysteine Concentrations Research Articles

MTHFR 677C→T genotype is associated with folate and homocysteine concentrations in a large, population-based, double-blind trial of folic acid supplementation

The methylenetetrahydrofolate reductase (MTHFR) genotype is associated with modification of disease and risk of neural tube defects. Plasma and red blood cell (RBC) folate and plasma homocysteine concentrations change in response to daily intakes of folic acid supplements, but no large-scale or population-based randomized trials have examined whether the MTHFR genotype modifies the observed response. We sought to determine whether the MTHFR 677C→T genotype modifies the response to folic acid supplementation during and 3 mo after discontinuation of supplementation. Northern Chinese women of childbearing age were enrolled in a 6-mo supplementation trial of different folic acid doses: 100, 400, and 4000 μg/d and 4000 μg/wk. Plasma and RBC folate and plasma homocysteine concentrations were measured at baseline; after 1, 3, and 6 mo of supplementation; and 3 mo after discontinuation of supplementation. MTHFR genotyping was performed to identify a C→T mutation at position 677 (n = 932). Plasma and RBC folate and homocysteine concentrations were associated with MTHFR genotype throughout the supplementation trial, regardless of folic acid dose. MTHFR TT was associated with lower folate concentrations, and the trend of TT < CC was maintained at even the highest doses. Folic acid doses of 100 μg/d or 4000 μg/wk did not reduce high homocysteine concentrations in those with the MTHFR TT genotype. MTHFR genotype was an independent predictor of plasma and RBC folate and plasma homocysteine concentrations and did not have a significant interaction with folic acid dose during supplementation. This trial was registered at clinicaltrials.gov as NCT00207558.

High bone concentrations of homocysteine are associated with altered bone morphology in humans

Accumulation of homocysteine and S-adenosylhomocysteine in bone has been shown to be associated with reduced bone quality in rats. The aim of the present study was to investigate whether high bone concentrations of homocysteine and S-adenosylhomocysteine as well as a low methylation capacity are related to an impaired bone morphology in humans. Concentrations of homocysteine and its precursors S-adenosylhomocysteine and S-adenosylmethionine were measured in femoral bone samples of eighty-two males and females (age 71 (SD 8) years) who underwent elective hip arthroplasty. Cancellous bone structure was analysed by histomorphometry. In addition, blood was sampled to measure serum concentrations of homocysteine. Results of bone and serum analyses were grouped for individuals with high or low bone concentrations of homocysteine, S-adenosylhomocysteine and S-adenosylmethionine, as well as for individuals with a high or a low methylation capacity, which is indicated by a low or a high S-adenosylhomocysteine:S-adenosylmethionine ratio (n 41, each). Histomorphometry showed a higher trabecular separation and a lower trabecular thickness, trabecular number and trabecular area in individuals with high bone concentrations of homocysteine and S-adenosylhomocysteine compared with individuals with low bone concentrations of homocysteine and S-adenosylhomocysteine. There was no association between the S-adenosylhomocysteine:S-adenosylmethionine ratio and bone morphology. It was found that 48 % of bone homocysteine was bound to the collagen of the extracellular bone matrix. Blood analyses demonstrated a significant correlation between serum and bone homocysteine. The results of the present study indicate an association between altered bone morphology and elevated bone concentrations of homocysteine and S-adenosylhomocysteine, but not between altered bone morphology and methylation capacity.

Genetic Polymorphism of Methylenetetrahydrofolate Reductase (MTHFR) and Coronary Artery Disease.

A high plasma homocysteine concentration is a risk factor for atherosclerotic disease and venous thrombosis. Homocysteine levels are influenced by folic acid, vitamin B 6 and vitamin B 12, as well as by hereditary factors. A common genetic variant of the methylenetetrahydrofolate reductase (MTHFR) gene CC 677 T) is associated with thermolability of the MTHFR enzyme and elevated plasma homocysteine concentration, especially in those with low folic acid concentration. The prevalence of point mutation (nucleotide 677 C --> T) in MTHFR was measured in patients with coronary artery disease (CAD) who all underwent coronary artery bypass surgery (62 cases; age 64.0 +/- 9.5 years), and was compared with, age-matched control subjects. In patients with coronary artery disease (CAD), we investigated the prevalence of point mutation (nucleotide 677 C --> T) in MTHFR in comparison with control subjects. Heterozygous (C/T) prevalence for the 677 C --> T mutation in the MTHFR was higher in patients with CAD than in control subjects (P < 0.05). The prevalence of homozygosity (C/C) for wild-type MTHFR was lower in patients with CAD in comparison with control subjects (P < 0.05).

Homocysteine and Familial Longevity: The Leiden Longevity Study

Homocysteine concentrations are a read-out of methionine metabolism and have been related to changes in lifespan in animal models. In humans, high homocysteine concentrations are an important predictor of age related disease. We aimed to explore the association of homocysteine with familial longevity by testing whether homocysteine is lower in individuals that are genetically enriched for longevity. We measured concentrations of total homocysteine in 1907 subjects from the Leiden Longevity Study consisting of 1309 offspring of nonagenarian siblings, who are enriched with familial factors promoting longevity, and 598 partners thereof as population controls. We found that homocysteine was related to age, creatinine, folate, vitamin B levels and medical history of hypertension and stroke in both groups (all p<0.001). However, levels of homocysteine did not differ between offspring enriched for longevity and their partners, and no differences in the age-related rise in homocysteine levels were found between groups (p for interaction 0.63). The results suggest that homocysteine metabolism is not likely to predict familial longevity.

Polyneuropathy and dementia in old age: common inflammatory and vascular parameters

Thirty-three inpatients (22 females, 11 males, aged 79.4 ± 9.5 years) were investigated in this prospective cohort study to study the prevalence of polyneuropathy (PNP) and dementia in geriatric inpatients. Clinical and electrodiagnostic investigations, routine laboratory, including thyroid parameters, folic acid, vitamin B(12), homocysteine, neopterin, fibrinogen and glycosylated hemoglobin were measured in serum, the mini-mental state examination and computed tomographic scanning were performed in each patient. PNP was found clinically and electrodiagnostically in 96% of patients. Age was the most precipitating factor for PNP, and was significantly correlated to electrodiagnostic changes in the nerves investigated in both, upper and lower extremities, while clinical symptoms were confined only to the feet. Correlation was seen between homocysteine and the amplitude of the sural nerve (surAmpl) (rs = -0.406, p = 0.029) as well as the sural nerve conduction velocity (surNCV) (rs = -0.389, p = 0.037), and between neopterin and the grade of denervation (rs = 0.445, p = 0.014) in our patients. Neopterin and fibrinogen did not correlate significantly, but there was a trend to higher fibrinogen concentrations in patients with higher neopterin levels (rs = 0.344, p = 0.062). A trend of a correlation was seen between higher homocysteine concentrations and the number of changes in electrodiagnostic measurements (rs = 0.354, p = 0.055). Twenty-one of the 33 patients (64%) were demented, 9 (27%) presented clinically as mild cognitive impairment, 3 (9%) were not demented. Vascular risk factors were found in 83%: hypertension in 58%, hypercholesterinemia in 39%, cardiac disease in 36%, diabetes mellitus (DM) in 21%, peripheral arterial disease (PAD) in 9%. A significant correlation was found between homocysteine and folic acid concentrations (rs = -0.401, p = 0.028). Falls were reported in 48% of cases, indicating PNP as a risk factor in this group of patients. In conclusion, PNP was found very common with a high coincidence with dementia and a female preponderance, suggesting an influence on daily life (falls) in our subjects studied. PNP correlated significantly with markers for vascular disease as well as immune activation (homocysteine and neopterin) similar to earlier findings in patients with neurodegenerative disorders, suggesting common therapeutic options in patients with PNP and dementia.

NOX2, p22phox and p47phox are Targeted to the Nuclear Pore Complex in Ischemic Cardiomyocytes Colocalizing with Local Reactive Oxygen Species

Background: NADPH oxidases play an essential role in reactive oxygen species (ROS)-based signaling in the heart. Previously, we have demonstrated that (peri)nuclear expression of the catalytic NADPH oxidase subunit NOX2 in stressed cardiomyocytes, e.g. under ischemia or high concentrations of homocysteine, is an important step in the induction of apoptosis in these cells. Here this ischemia-induced nuclear targeting and activation of NOX2 was specified in cardiomyocytes. Methods: The effect of ischemia, mimicked by metabolic inhibition, on nuclear localization of NOX2 and the NADPH oxidase subunits p22^phox and p47^phox, was analyzed in rat neonatal cardiomyoblasts (H9c2 cells) using Western blot, immuno-electron microscopy and digital-imaging microscopy. Results: NOX2 expression significantly increased in nuclear fractions of ischemic H9c2 cells. In addition, in these cells NOX2 was found to colocalize in the nuclear envelope with nuclear pore complexes, p22^phox, p47^phox and nitrotyrosine residues, a marker for the generation of ROS. Inhibition of NADPH oxidase activity, with apocynin and DPI, significantly reduced (peri)nuclear expression of nitrotyrosine. Conclusion: We for the first time show that NOX2, p22^phox and p47^phox are targeted to and produce ROS at the nuclear pore complex in ischemic cardiomyocytes.

Serum Homocysteine and Folate Levels in Korean Schizophrenic Patients

ObjectiveThis study was conducted to confirm the results of the authors' previous research on schizophrenia manifesting high serum homocysteine and low folate levels. This study is anchored on a theory that a high serum homocysteine concentration affects schizophrenia by virtue of a neurotoxic mechanism, and on a report that some schizophrenia patients with high homocysteine levels benefited from high folate ingestion.MethodsThe serum homocysteine, folate, and vitamin B12 levels of 236 normal-control-group subjects and 234 schizophrenia subjects who met the diagnostic criteria based on DSM-IV-TR were compared. The homocysteine levels were measured via fluorescence polarization immunoassay, and the folate and vitamin B12 levels were determined via radioimmunoassay.ResultsThe homocysteine levels of the patient group were significantly higher than those of the normal control group. The homocysteine level was more negatively correlated with the folate level in the schizophrenia group than in the control group. The percentages of female and male schizophrenia subjects manifesting high homocysteine levels were 33.8 and 51.5%, respectively. The percentage of schizophrenia subjects with low folate levels was 66.2%. In the low- and normal-folate-level groups, the patient group showed significantly higher homocysteine levels than the normal control group. The low-folate-level patient group particularly showed significantly higher homocysteine levels than the low-folate-level normal control group.ConclusionSome schizophrenia patients with high serum homocysteine levels may have the genetic defect of having low folate serum levels. In such cases, folate ingestion may be a good management modality for clinical improvement.

Increased Homocysteine in a Patient Diagnosed with Marfan Syndrome

A 53-year-old Caucasian woman was diagnosed in late childhood with Marfan syndrome according to characteristic skeletal features and bilateral lens dislocation. In addition, she has a history of nonischemic cardiomyopathy with severe left ventricular failure and atrial fibrillation, diabetes mellitus type 2, hyperlipidemia, progressive dementia, numbness in the lower extremities, and hypothyroidism following thyroidectomy for thyroid cancer. Additional findings revealed in a physical examination included an upper-to-lower segment ratio of 0.88, an arm span–to–height ratio of 1.02 (an upper-to-lower–segment ratio 1.05 are 2 of the diagnostic criteria for Marfan syndrome), an elongated face, a high arched palate, and crowded dentition. She recently underwent further laboratory testing after a cardiologist did not find 2 characteristic features of Marfan syndrome, namely an enlarged aortic root and mitral valve prolapse. Her total plasma homocysteine and methionine concentrations were increased at 198 μmol/L (reference interval, 5–15 μmol/L) and 370 μmol/L (reference interval, 10–50 μmol/L), respectively. The patient's plasma homocystine concentration was 48 μmol/L (reference interval, <2 μmol/L), and her urine homocystine concentration was also markedly increased. These biochemical abnormalities are not characteristic of Marfan syndrome. Her diagnosis was reconsidered in light of these new data. In this case, a long-standing clinical diagnosis was inconsistent with recently obtained clinical and biochemical data. The biochemical data were virtually diagnostic of homocystinuria [OMIM3 (Online Mendelian Inheritance in Man) 236200], a term historically used to describe inborn errors of metabolism characterized by excessive excretion of homocystine in urine and high concentrations of total plasma homocysteine. Homocystinuria is most commonly caused by autosomal recessive inheritance of a deficiency in cystathionine β-synthase (CBS) activity (1). The worldwide incidence has been estimated to be between 1 in 200 000 and 1 in 335 000 population (2), with the highest incidence (1 in 1800) reported in Qatar …

Analysis of serum levels of homocysteine and oxidative stress markers in patients with Alzheimer disease

Alzheimer disease is the most common degenerative disorders of the brain. High concentrations of homocysteine, a sulfhydryl amino acid produced by the methionine cycle, have been linked to an increased risk of Alzheimer disease. The mechanism by which homocysteine contributes to the pathogenesis of Alzheimer disease is unknown; although it has been proposed that hyperhomocysteinemia produces changes in the structure and function of cerebral blood vessels and neurons and oxidative stress appears to play a major role in mediating these changes. Besides, homocysteine levels are influenced by vitamin B 12 and folate and seem to be modifiable through B vitamin supplementation. We wanted to verify whether some parameters are increased in patients with Alzheimer disease. In our study, we measured the levels of total homocysteine and the main oxidative stress markers (cysteine, thiol groups, malondialdehyde and purine metabolites) in blood samples from patients with Alzheimer disease, taking vitamin B 12 and folate supplements and from age-matched controls in order to evaluate the possible correlation between homocysteine and the main oxidative stress markers. We also measured vitamin B 12 and folate levels in order to verify their influence on homocysteine concentration. Our results show an increase in hypoxanthine, xanthine, homocysteine and cysteine levels in both patients with Alzheimer disease and the control group. The increase seems essentially related to age, rather than to the specific disease.

Genetic and lifestyle variables associated with homocysteine concentrations and the distribution of folate derivatives in healthy premenopausal women

Low folate and high homocysteine (Hcy) concentrations are associated with pregnancy-related pathologies such as spina bifida. Polymorphisms in folate/Hcy metabolic enzymes may contribute to this potentially pathogenic biochemical phenotype. The study comprised 26 Caucasian and 23 African-American premenopausal women. Subjects gave fasting blood samples for biochemical phenotyping and genotyping. Total Hcy (tHcy) and both plasma and red blood cell (RBC) folate derivatives (i.e. tetrahydrofolate [THF], 5-methylTHF [5-MTHF], and 5,10-methenylTHF [5,10-MTHF]) were measured using stable isotope dilution liquid chromatography, multiple reaction monitoring, and mass spectrometry. Eleven polymorphisms from nine folate/Hcy pathway genes were genotyped. Tests of association between genetic, lifestyle, and biochemical variables were applied. In African American women, tHcy concentrations were associated (p < 0.05) with total RBC folate, RBC 5-MTHF, B(12), and polymorphisms in methionine synthase (MTR) and thymidylate synthase (TYMS). In Caucasian women, tHcy concentrations were not associated with total folate levels, but were associated (p < 0.05) with RBC THF, ratios of RBC 5-MTHF:THF, and polymorphisms in 5,10-methylenetetrahydrofolate reductase (MTHFR) and MTR. In African Americans, folate derivative levels were associated with smoking, B(12), and polymorphisms in MTR, TYMS, methionine synthase reductase (MTRR), and reduced folate carrier1 (RFC1). In Caucasians, folate derivative levels were associated with vitamin use, B(12), and polymorphisms in MTHFR, TYMS, and RFC1. Polymorphisms in the folate/Hcy pathway are associated with tHcy and folate derivative levels. In African American and Caucasian women, different factors are associated with folate/Hcy phenotypes and may contribute to race-specific differences in the risks of a range of pregnancy-related pathologies.

CD46-associated atypical hemolytic uremic syndrome with uncommon course caused by cblC deficiency

CD46-associated atypical hemolytic uremic syndrome with uncommon course caused by cblC deficiency

Plasma Thiols and Taurine Levels in Central Retinal Vein Occlusion

Purpose: To determine the plasma levels of the sulfur-containing amino-acids homocysteine, cysteine, cysteinylglycine, glutamylcysteine, glutathione, and taurine in patients with central retinal vein occlusion (CRVO) and in healthy subjects and to ascertain whether there are statistically significant differences between patients and controls.Methods: Laser-induced fluorescence capillary electrophoresis was used to measure the plasma levels of homocysteine, cysteine, cysteinylglycine, glutamylcysteine, glutathione, and taurine in 29 patients with CRVO and 80 age- and gender-matched control subjects. Wilcoxon or Student’s t-test was used, when appropriate, to determine differences between groups. Multivariate logistic regression analysis was used to determine the risks for CRVO.Results: CRVO patients showed significantly higher concentrations of cysteine (p = 0.032) and significantly lower concentrations of cysteinylglycine (p = 0.009) and taurine (p = 0.0002) than controls. Conversely, there were no significant differences in plasma homocysteine, glutamylcysteine, and glutathione between CRVO patients and controls. When categorized by CRVO type (ischemic/non-ischemic), taurine was still lower in both subgroups than in controls, whereas cysteine, cysteinylglycine, as well as homocysteine, were significantly higher only in the ischemic subgroup. In non-ischemic CRVO, cysteinylglycine fell just short of statistical significance (p = 0.06). Logistic regression analysis revealed an odds ratio of 1.02 (95% confidence interval (CI): 1.01–1.04, p = 0.001) for cysteine, 0.79 (95% CI: 0.70–0.89, p = 0.0002) for cysteinylglycine, and 0.94 (95% CI: 0.90–0.97, p = 0.002) for taurine.Conclusions: Results suggest that reduced plasma levels of cysteinylglycine and taurine may contribute to the pathogenesis of both CRVO types. Furthermore, this study also demonstrated an association between ischemic CRVO and higher concentrations of homocysteine and cysteine.

Serum Adiponectin, Leptin, C-Peptide, Homocysteine, and Colorectal Adenoma Recurrence in the Polyp Prevention Trial

Serum adiponectin, leptin, C-peptide, and homocysteine are indicators for obesity, hyperinsulinemia, and chronic inflammation, which have all been associated with colorectal cancer. To determine whether serum adiponectin, leptin, C-peptide, and homocysteine are associated with fat, fiber, fruit and vegetable, flavonol, or dry bean intake and colorectal adenoma recurrence. Using logistic regression, we estimated odds ratios (OR) and 95% confidence intervals (95% CI) for adenoma recurrence in 627 participants from the control arm of the Polyp Prevention Trial, a 4-year trial that examined the effectiveness of a low-fat, high-fiber, high-fruit and vegetable diet on adenoma recurrence. Serum concentrations of C-peptide and homocysteine were inversely related to fiber, fruit and vegetable, and flavonol intake and positively related to percentage of calories from fat (all P(trend) < or = 0.01). High homocysteine concentrations were associated with any (4th versus 1st quartile: OR, 2.26; 95% CI, 1.30-3.94) and more than one adenoma recurrence (OR, 2.11; 95% CI, 1.01-4.40). Individuals in the highest, versus lowest, tertile of serum leptin concentration had a decreased risk of advanced adenoma recurrence (OR, 0.22; 95% CI, 0.06-0.79). Our results suggest that serum homocysteine may serve as an indicator of dietary exposure, including a low-fat and high-fiber, high-fruit and vegetable, and high-flavonol diet, as well as colorectal adenoma recurrence. Discovering biomarkers that are both modifiable and can predict cancer risk is critical. We identified serum homocysteine as a novel indicator that is modified by diet and predicts risk of adenoma recurrence.

Lack of Association Between Total Serum Homocysteine and Extracranial Cerebral Flow

High homocysteine (Hcy) concentration is associated with slow coronary flow. This study examined the association between Hcy and hemodynamic status in the extracranial cerebral arteries in healthy individuals. A total of 535 healthy adults underwent physical examination and duplex ultrasonography of the extracranial carotid and vertebral arteries, and blood laboratory tests, including biochemistry and serum total Hcy. Flow hemodynamic parameters including velocity, resistance, and volume of the carotid and vertebral arteries were measured. Multiple regression analysis was performed to examine the association between Hcy and the flow parameters. Participants with higher Hcy were more likely to have a lower systolic velocity of the internal carotid artery (p = 0.01) and vertebral artery (p < 0.001), and lower resistance of the vertebral artery (p = 0.004). However, the multiple-adjusted means of the flow velocity, resistance, and flow volume of the carotid or vertebral artery were not significantly different across quartiles of Hcy. When Hcy was treated as a continuous variable, there was still no significant relationship between Hcy levels and the aforementioned hemodynamic status. Our results did not support the hypothesis that the levels of Hcy are associated with the flow velocity, resistance, and volume of the extracranial cerebral artery in healthy individuals.

Expression of methylation pathway enzymes in bovine oocytes and preimplantation embryos

The methylation pathway, which consists of two metabolic cycles of nutrients, i.e., the methionine and folate cycles, generates S-adenosylmethionine, the methyl donor for the methylation of DNA and histones. Using reverse transcription-polymerase chain reaction, we examined the gene expression patterns of the methylation pathway enzymes during bovine oocyte maturation and preimplantation embryonic development up to the blastocyst stage. Bovine oocytes were demonstrated to have the mRNA of all methylation pathway enzymes examined, namely, methionine adenosyltransferase 1A (MAT1A), MAT2A, MAT2B, S-adenosylhomocysteine hydrolase (AHCY), 5-methyltetrahydrofolate-homocysteine methyltransferase (MTR), betaine-homocysteine methyltransferase (BHMT), serine hydroxymethyltransferase 1 (SHMT1), SHMT2, and 5,10-methylenetetrahydrofolate reductase (MTHFR). All the transcripts were consistently expressed throughout all developmental stages, except for MAT1A, which was not detected from the 8-cell stage onward and BHMT, which was not detected in the 8-cell stage. Immunofluorescence analysis of MAT1A protein revealed the relatively higher expression in oocytes and early cleavage stage embryos up to the 8-cell stage compared with the morula and blastocyst stage. Further, to investigate the effects of methylation pathway disruption during the earliest stages of embryonic development, the effects of exogenous homocysteine on preimplantation development and DNA methylation of bovine embryos were investigated in vitro. As results, high concentrations of homocysteine induced hypermethylation of genomic DNA as well as developmental retardation in bovine embryos. These results provide a new insight into nutrient-sensitive epigenetic regulation and perturbation at the earliest stage of our life.

Total homocysteine in patients with angiographic coronary artery disease correlates with inflammation markers

Moderate hyperhomocysteinaemia is considered as an independent risk marker for cardiovascular disease and stroke. Earlier, increased homocysteine production was detected in stimulated immunocompetent cells in vitro, and several markers of inflammation like neopterin or C-reactive protein (CRP) were demonstrated as significant indicators of cardiovascular risk. The relationship between coronary artery disease (CAD), homocysteine metabolism and markers of immune activation and inflammation was investigated in a population of 1717 patients undergoing coronary angiography, recruited as participants of the LUdwigshafen RIsk and Cardiovascular Health (LURIC) study. 1325 patients (77.2%) suffered from coronary artery disease (CAD), which was was defined as the occurrence of a visible luminal narrowing (>or=20% stenosis) in at least 1 of 15 coronary segments according to the classification of the American Heart Association, the remaining 392 individuals of the study population served as controls. Significant differences regarding systolic blood pressure, homocysteine, neopterin and folic acid concentrations were observed between patients and controls. Older age, decreased creatinine-clearance and higher concentrations of homocysteine and CRP were indicative for CAD. Low B-vitamin availability, therapy and the extent of immune activation strongly influenced homocysteine concentrations. Homocysteine concentrations were correlated with neopterin levels (r(s) =0.325, p<0.001), and hyperhomocysteinaemic patients also presented with significantly higher CRP concentrations. Homocysteine accumulation coincided with impaired renal and heart function (as reflected by ProBNP[Brain natriuretic peptide]-concentrations). We conclude that homocysteine accumulation could result from B-vitamin deficiency which is related to chronic immune activation.

Tratamientos vitamínicos para disminuir la concentración de homocisteína: ¿reducen el riesgo de enfermedad cerebrovascular en prevención primaria?

High plasma homocysteine (Hcy) concentration or hyperhomocysteinemia is associated with an increased vascular risk of disease in case-control studies and, to a lesser extent, in prospective studies. Several large randomized, double-blind, placebo-controlled trials have been already conducted using specific vitamin therapies with the aim of reducing secondary cardiovascular (HOPE, NORVIT, WAFACS and WENBIT studies) and cerebrovascular (VISP study) disease risk. The results from these major secondary prevention trials and one meta-analysis, that included other smaller studies up to 12 of them, showed that treatment decreased plasma Hcy concentration but failed to reduce cardiovascular risk. It is nevertheless noteworthy that a recent meta-analysis addressing the effects of these vitamin treatments on cerebrovascular risk found a positive effect on primary stroke prevention. These data would be consistent with the fact that increased Hcy is known to be associated more strongly with stroke risk than with cardiovascular risk. Moreover, folic acid supplementation in grain food has recently been shown to be associated with a decreased stroke incidence in USA and Canada. Obviously, these data on primary stroke prevention will require extensive confirmation. However, there now appear to be more reasons to expect a positive outcome of Hcy intervention studies.

Age-dependent decreases in DNA methyltransferase levels and low transmethylation micronutrient levels synergize to promote overexpression of genes implicated in autoimmunity and acute coronary syndromes

T cell DNA methylation levels decline with age, activating genes such as KIR and TNFSF7 (CD70), implicated in lupus-like autoimmunity and acute coronary syndromes. The mechanisms causing age-dependent DNA demethylation are unclear. Maintenance of DNA methylation depends on DNA methyltransferase 1 (Dnmt1) and intracellular S-adenosylmethionine (SAM) levels, and is inhibited by S-adenosylhomocysteine (SAH). SAM levels depend on dietary micronutrients including folate and methionine. SAH levels depend on serum homocysteine concentrations. T cell Dnmt1 levels also decline with age. We hypothesized that age-dependent Dnmt1 decreases synergize with low folate, low methionine or high homocysteine levels to demethylate and activate methylation-sensitive genes. T cells from healthy adults ages 22–81, stimulated and cultured with low folate, low methionine, or high homocysteine concentrations showed demethylation and overexpression of KIR and CD70 beginning at age ∼50 and increased further with age. The effects were reproduced by Dnmt1 knockdowns in T cells from young subjects. These results indicate that maintenance of T cell DNA methylation patterns is more sensitive to low folate and methionine levels in older than younger individuals, due to low Dnmt1 levels, and that homocysteine further increases aberrant gene expression. Thus, attention to proper nutrition may be particularly important in the elderly.

Metabolic evidence of vitamin B-12 deficiency, including high homocysteine and methylmalonic acid and low holotranscobalamin, is more pronounced in older adults with elevated plasma folate

BackgroundAn analysis of data from the National Health and Nutrition Examination Survey indicated that in older adults exposed to folic acid fortification, the combination of low serum vitamin B-12 and elevated folate is associated with higher concentrations of homocysteine and methylmalonic acid and higher odds ratios for cognitive impairment and anemia than the combination of low vitamin B-12 and nonelevated folate. These findings await confirmation in other populations. ObjectiveThe purpose was to compare metabolic indicators of vitamin B-12 status, cognitive function, and depressive symptoms among elderly Latinos with elevated and nonelevated plasma folate. DesignCross-sectional data were analyzed for 1535 subjects (age: ≥60 y) from the Sacramento Area Latino Study on Aging. Subjects were divided into 4 groups on the basis of plasma vitamin B-12 (< or ≥148 pmol/L) and folate (≤ or >45.3 nmol/L). Homocysteine, methylmalonic acid, holotranscobalamin, ratio of holotranscobalamin to vitamin B-12, Modified Mini-Mental State Examination, delayed recall, and depressive symptom scores were compared between the groups. ResultsIndividuals with low vitamin B-12 and elevated folate (n = 22) had the highest concentrations of homocysteine and methylmalonic acid and the lowest concentration of holotranscobalamin and ratio of holotranscobalamin to vitamin B-12 when compared with all other groups (P ≤ 0.003). No differences in Modified Mini-Mental State Examination, delayed recall, and depressive symptom scores were observed between the low vitamin B-12 and elevated-folate group compared with other groups. ConclusionsLow vitamin B-12 is associated with more pronounced metabolic evidence of vitamin B-12 deficiency when folate is elevated than when folate is not elevated. These data should be considered when assessing the potential costs, risks, and benefits of folic acid and vitamin B-12 fortification programs.

High plasma homocysteine levels contribute to the risk of stroke recurrence and all-cause mortality in a large prospective stroke population

Plasma homocysteine concentrations have been associated with the risk of stroke, but its relevance to secondary vascular events and mortality after stroke remains unclear because of inconsistent results from clinical trials. The aim of the present study was to investigate whether plasma homocysteine levels and the MTHFR (methylenetetrahydrofolate reductase) variant C677T contributed to the risk of stroke recurrence and all-cause mortality in a large prospective cohort of stroke patients in a Chinese population. A total of 1823 stroke patients (age, 35-74 years) were recruited during 2000-2001 and prospectively followed-up for a median of 4.5 years. During the follow-up, 347 recurrent strokes and 323 deaths from all-causes were documented. After adjustment for age, gender and other cardiovascular risk factors, a high homocysteine concentration was associated with an increased risk of 1.74-fold for stroke recurrence {RR (relative risk), 1.74 [95% CI (confidence interval), 1.3-2.3]; P<0.0001} and 1.75-fold for all-cause mortality [RR, 1.75 (95% CI, 1.3-2.4); P<0.0001] when highest and lowest categories were compared. Spline regression analyses revealed a threshold level of homocysteine for stroke recurrence. By dichotomizing homocysteine concentrations, the RRs were 1.31 (95% CI, 1.10-1.61; P=0.016) for stroke recurrence and 1.47 (95% CI, 1.15-1.88; P<0.0001) for all-cause mortality in patients with homocysteine levels > or =16 micromol/l relative to those with levels <16 micromol/l. The association of elevated plasma homocysteine concentrations with all-cause mortality was mainly due to an increased risk of cardiovascular deaths. No significant association was found between MTHFR C677T and stroke recurrence or mortality. In conclusion, our findings suggest that elevated homocysteine concentrations can predict the risk of stroke recurrence and mortality in patients with stroke.