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Introduction: Observational studies identified plasma homocysteine as a risk factor for ischemic stroke, but randomized controlled trials of folate supplementation reported inconsistent findings. The methylenetetrahydrofolate reductase ( MTHFR) gene encodes an enzyme critical for homocysteine metabolism and can serve as an unconfounded proxy for plasma homocysteine levels. Hypothesis: We assessed the hypothesis that there was a causal association between plasma homocysteine and risk of ischemic stroke by Mendelian randomization method. Methods: We examined the association between the MTHFR gene and ischemic stroke among 11,753 Chinese participants. The discovery stage included 999 ischemic stroke cases and 1,001 controls with no history of atherosclerotic disease. The MTHFR gene was sequenced using the SOLiD 4hq platform. Variants with minor allele count >10 were each tested for association with stroke using logistic regression models. Interactions between significant variants and alcohol drinking on stroke were also tested. Aggregate analysis of rare variants (minor allele count -4 were tested for replication among 4,724 ischemic stroke cases and 5,029 controls from the China Stroke Project. Results: An association between MTHFR rs1801133, a missense variant known to reduce enzyme activity and increase plasma homocysteine level, and ischemic stroke was identified in discovery, replication and joint analyses (P=2.10х10 -8 , 2.65х10 -11 , and 6.93х10 -17 , respectively). Each copy of the rs1801133 risk allele conferred respective odds ratios (95% confidence interval) of 1.44 (1.27, 1.64), 1.21 (1.15, 1.28), and 1.25 (1.18, 1.31). This variant also interacted with alcohol intake on stroke risk (P for interaction=7.82х10 -9 , 1.86х10 -10 , and 1.46х10 -18 , respectively). Odds ratios (95% confidence interval) of stroke associated with the risk allele were 1.66 (1.40, 1.96), 1.26 (1.18, 1.36), and 1.32 (1.23, 1.40) in non-drinkers and 1.17 (0.92, 1.49), 1.12 (1.01, 1.23), and 1.12 (1.03, 1.23) among alcohol drinkers in discovery, replication and joint analyses, respectively. No additional variants were identified. Conclusions: In conclusion, this is the first large scale genomic study to implicate the etiologic relevance of plasma homocysteine in ischemic stroke. An attenuating effect of alcohol intake on this relation was also observed.

Introduction: Observational studies identified plasma homocysteine as a risk factor for ischemic stroke, but randomized controlled trials of folate supplementation reported inconsistent findings. The MTHFR gene encodes an enzyme critical for homocysteine metabolism and can serve as an unconfounded proxy for plasma homocysteine levels. We examined the association between the MTHFR gene and ischemic stroke among 11,753 Chinese participants. Methods: The discovery stage included 999 ischemic stroke cases and 1,001 controls with no history of atherosclerotic disease. The MTHFR gene was sequenced using the SOLiD 4hq platform. Variants with minor allele count (MAC) >10 were each tested for association with stroke using logistic regression models. Interactions between significant variants and alcohol drinking on stroke were also tested. Aggregate analysis of rare variants (MAC -4 were tested for replication among 4,724 ischemic stroke cases and 5,029 controls from the China Stroke Project. Results: An association between MTHFR rs1801133, a missense variant known to reduce enzyme activity and increase plasma homocysteine level, and ischemic stroke was identified in discovery, replication and joint analyses (P=2.10х10 -8 , 2.65х10 -11 , and 6.93х10 -17 , respectively). Each copy of the rs1801133 risk allele conferred respective odds ratios (95% CI) of 1.44 (1.27, 1.64), 1.21 (1.15, 1.28), and 1.25 (1.18, 1.31). This variant also interacted with alcohol intake on stroke risk (P for interaction=7.82х10 -9 , 1.86х10 -10 , and 1.46х10 -18 , respectively). Odds ratios (95% CI) of stroke associated with the risk allele were 1.66 (1.40, 1.96), 1.26 (1.18, 1.36), and 1.32 (1.23, 1.40) in non-drinkers and 1.17 (0.92, 1.49), 1.12 (1.01, 1.23), and 1.12 (1.03, 1.23) among alcohol drinkers in discovery, replication and joint analyses, respectively. No additional variants were identified. Conclusions: This is the first large scale genomic study to implicate the etiologic relevance of plasma homocysteine in ischemic stroke. An attenuating effect of alcohol intake on this relation was also observed.

Objective:Cushing's syndrome and subclinical hypercortisolism are associated with a hypercoagulable state. In patients with hypertension, a prothrombotic state and elevated plasma homocysteine (Hcy) are associated with presence and severity of organ damage. In this study, we examined the relationshi

Background:Nitrous oxide causes an acute increase in plasma homocysteine that is more pronounced in patients with the methylenetetrahydrofolate reductase (MTHFR) C677T or A1298C gene variant. In this randomized controlled trial, the authors sought to determine whether patients carrying the MTHFR C677T or A1298C variant had a higher risk for perioperative cardiac events after nitrous oxide anesthesia and whether this risk could be mitigated by B-vitamins.Methods:The authors randomized adult patients with cardiac risk factors undergoing noncardiac surgery, to receive nitrous oxide plus intravenous B-vitamins before and after surgery, or to nitrous oxide and placebo. Serial cardiac biomarkers and 12-lead electrocardiograms were obtained. The primary study endpoint was the incidence of myocardial injury, as defined by cardiac troponin I increase within the first 72 h after surgery.Results:A total of 500 patients completed the trial. Patients who were homozygous for either MTHFR C677T, or A1298C gene variant (n = 98; 19.6%) had no increased rate of postoperative cardiac troponin I increase compared with wild-type and heterozygous patients (11.2 vs. 14.0%; relative risk 0.96; 95% CI, 0.85–1.07; P = 0.48). B-vitamins blunted the rise in homocysteine, but had no effect on cardiac troponin I increase compared with patients receiving placebo (13.2 vs. 13.6%; relative risk 1.02; 95% CI 0.78 to 1.32; P = 0.91).Conclusions:Neither MTHFR C677T and A1298C gene variant, nor acute homocysteine increase are associated with perioperative cardiac troponin increase after nitrous oxide anesthesia. B-vitamins blunt nitrous oxide-induced homocysteine increase but have no effect on cardiac troponin I increase.

INTRODUCTION Hyperhomocystenemia (HHcy) is a risk factor for thrombosis in adults. Polymorphisms in methylene tetrahydrofolate reductase (MTHFR) enzyme may cause HHcy. Data on their role in pediatric thromboembolism (TE) are sparse. MATERIALS AND METHODS Charts of patients from 1989 to 2007, with documented TE, were reviewed. Homocysteine (Hcy) levels were defined both as per the adult normal range and the age-specific normal ranges from literature. RESULTS A total of 141 patients (67 females, 74 males) were identified. With age-specific normal ranges for Hcy, 15 patients were found to have HHcy: 6 had CT, 9 patients had CC, and none had TT MTHFR genotype. When adult normal range was used, HHcy (>12 μmol/L) was seen in 7 patients: 4 had CT and 3 had the CC genotype. Again, none had TT genotype. In addition, the mean Hcy levels were unaffected by sex and ethnicities, but universal folic acid supplementation (post 1996) lowered the mean. CONCLUSIONS (1) Age-specific ranges for Hcy should be used in pediatrics for accurate diagnosis of HHcy. (2) MTHFR C677T polymorphism is not a risk factor in pediatric TE. (3) Folic acid supplementation could play a role in lowering the prevalence of HHcy.

PURPOSE To investigate whether there is an association of elevated plasma levels of homocysteine (Hcy) and normal tension glaucoma (NTG). PATIENTS AND METHODS Plasma levels of Hcy (fluorescence polarization immunoassay), vitamin B6 (high-performance liquid chromatography), vitamin B12, and folate levels (immunoassay) were determined in 42 patients with NTG and in 42 age-matched and sex-matched controls. RESULTS No significant difference regarding Hcy (NTG: 10.95 μmol/L±2.65; controls: 11.29 μmol/L±2.76) (P=0.639), vitamin B6 (NTG: 14.45 ng/mL±12.89; controls: 13.57 ng/mL±10.41) (P=0.629), vitamin B12 (NTG: 387.73 pg/mL±282.04; controls: 423.27 pg/mL±188.85) (P=0.052) and folate (NTG: 9.45ng/mL±3.42; controls: 10.82 ng/mL±4.48) (P=0.181) levels were found between both groups. CONCLUSIONS An association of elevated Hcy levels and NTG was not found and therefore a role of Hcy as a modifiable risk factor in the pathogenesis of NTG seems unlikely.

Elevated plasma homocysteine has been associated with an increased risk of cardiovascular disease. The association between open-angle glaucoma and cardiovascular disease has recently stimulated interest in the role of homocysteine in the pathogenesis of glaucoma. Some studies report elevated plasma homocysteine in patients with pseudoexfoliation syndrome and pseudoexfoliation glaucoma (PXFG), but have not found this association consistently in other types of open-angle glaucoma. In this study, we have measured plasma homocysteine and C677T methylenetetrahydrofolate reductase (MTHFR) mutation, the commonest genetic cause of elevated plasma homocysteine, in patients with PXFG, primary open-angle glaucoma (POAG), and normal tension glaucoma (NTG).Prospective cross-sectional cohort study.Forty-eight patients with PXFG, 36 patients with POAG, 34 patients with NTG, and 42 controls without glaucoma.Fasting venous blood samples from each participant were analyzed for plasma homocysteine and the C677T MTHFR gene mutation. MAIN OUTCOME OF INTEREST: Mean plasma homocysteine levels, number of individuals with homocysteine above the reference range, and percentage of individuals with heterozygous or homozygous C677T MTHFR gene mutations.Mean plasma homocysteine was significantly higher in PXFG (11.77+/-4.18 micromol/L), POAG (11.21+/-2.84 micromol/L), and NTG (11.74+/-3.79 micromol/L) compared with control (9.82+/-1.75 micromol/L). Hyperhomocysteinemia was found in 27.1% of PXFG patients, 30.6% of POAG patients, and 29.4% of NTG patients. There was no significant difference in frequency of MTHFR C677T gene mutation between groups.Plasma homocysteine was elevated in PXFG, POAG, and NTG. Elevated plasma homocysteine seems to be associated with glaucoma in these patients.

Purpose of review To determine whether clinicians should continue to screen for or treat hyperhomocysteinemia among individuals with venous thromboembolism. Recent findings The present review addresses four questions: Is hyperhomocysteinemia a risk factor for venous thromboembolism? Are the genetic polymorphisms that cause hyperhomocysteinemia risk factors for venous thromboembolism? Does lowering plasma homocysteine alter the risk of venous thromboembolism? What should clinicians do? Summary There may be a modest association between mild-to-moderate hyperhomocysteinemia and venous thromboembolism risk. This may be partly explained by genetic polymorphisms that affect homocysteine metabolism. However, two randomized placebo-controlled trials have failed to show a significant reduction in the risk of venous thromboembolism by lowering plasma homocysteine.

BACKGROUND Numerous studies have shown a relationship between hyperhomocysteinemia, atherothrombosis and cardiovascular mortality. However, an association between hyperhomocysteinemia and the extent of coronary artery disease (CAD) remains controversial whereas its relationship with left ventricular systolic function has not been established. METHODS One hundred and fifty-seven patients with angiographically defined CAD were included. The relationships between hyperhomocysteinemia, severity of CAD and left ventricular systolic function were studied. Left ventricular systolic function was determined primarily by ventriculography. The severity of CAD was determined through coronary angiography using the Gensini score and the number of vessels with > or = 50% stenosis. RESULTS The mean fasting plasma homocysteine level was 13.4 mumol/l+/-0.5 SE. Elevated levels of homocysteine correlated significantly with increased severity of CAD both by the Gensini scores (r-value = 0.344, P < 0.0005) and the total number of diseased vessels (r-value = 0.387, P < 0.0005). The patients with hyperhomocysteinemia were found to have significantly reduced left ventricular ejection fraction (r-value = -0.382, P < 0.0005). A multivariate regression analysis revealed homocysteine level to be an independent predictor of left ventricular systolic function. In addition, adjusted analysis revealed hyperhomocysteinemia to be associated with global left ventricular dysfunction. CONCLUSION In patients with CAD, homocysteine levels correlate independently with left ventricular systolic function. The mechanism of this association between homocysteine and left ventricular systolic function is unknown but may be due to a direct effect of homocysteine on myocardial function separate from its effects on coronary atherosclerosis.

Purpose To compare plasma homocysteine levels between patients with dry eye disease and normal control subjects. Methods Plasma homocysteine (enzyme immunoassay), vitamin B12, and folate levels were determined in 38 patients with dry eye and in 38 controls. Results Characteristics of the dry eye and control groups were similar. The mean plasma homocysteine level was 16.38 ± 6.98 μmol/L in the dry eye group and 14.39 ± 5.11 μmol/L in the control group (P = 0.10, t test). Hyperhomocysteinemia was present in the 43.9% of the dry eye patients and 33.3% of the controls (P = 0.43, χ test). There were no statistical differences between dry eye and control groups regarding plasma vitamin B12 and folate levels (P = 0.72 and P = 0.69, respectively, t test). Conclusions Plasma homocysteine levels in dry eye patients may be inadequate to give homocysteine a role in pathogenesis. However, in ocular diseases like glaucoma, plasma homocysteine levels are significantly higher, and associated dry eye disease may cause an additional increase in plasma homocysteine levels.

OBJECTIVE Clinical and basic studies have provided evidence that the cardiovascular protective effects of estrogens are partly due to effects on vasoreactivity and changes in homocysteine metabolism. Moreover, homocysteine has also been shown to influence vasoreactivity. We investigated the influence of homocysteine on the rapid vasodilatory effects of estradiol in an isolated vessel setup. DESIGN Isolated, spontaneously constricted, gracilis muscle arterioles (diameter approximately 50 micromol/L) from female Wistar rats were cumulatively exposed to 10-10 to 10-4 mol/L 17beta-estradiol in the presence of 50 micromol/L homocysteine or N-nitro-L-arginine (L-NA) (a blocker of nitric oxide synthesis), or both. Control experiments were done without L-NA or homocysteine (n = 6 for each series). RESULTS The dose-dependent dilation during short-term exposure to 17beta-estradiol was significantly less or absent in arterioles where L-NA, homocysteine, or both were present. The addition of 50 micromol/L homocysteine significantly increased the spontaneous constriction by 6% to 10%. CONCLUSIONS We showed that a pathophysiological concentration of homocysteine increases the spontaneous arteriolar constriction and inhibits the 17beta-estradiol-induced, endothelium-mediated, rapid vasodilatory effect on muscle arterioles from the female rat. The endothelium-independent vasodilation remained unchanged.

Elevated plasma homocysteine is considered to be a graded risk factor for cardiovascular disease, and for this reason there is great interest in high-performance analytical techniques. Methods have evolved from ion-exchange chromatography to embrace high-performance liquid chromatography with fluorescence or electrochemical detection, immunoassays, gas chromatography-mass spectroscopy and liquid chromatography with tandem mass spectrometry. Immunoassays and high-performance liquid chromatography methods are currently available in kit form, fluorescence polarization immunoassay showing the best performance.

During the last years, many epidemiologic studies have identified homocysteine as an independent risk factor for cardiovascular diseases like coronary events, stroke, and venous thromboembolism. Supplementation with oral folate and vitamins B6 and B12 (mainly folate) reduce plasma homocysteine levels to a significant degree. Recent clinical trials showed that vitamin supplementation leads to slower progression or even regression of atherosclerotic lesions in the carotid arteries, as confirmed by ultrasonographic measurement of carotid intima media thickness. However, the recent Vitamin Intervention for Stroke Prevention (VISP) study failed to show any clinical effect on stroke prevention. It is unclear if homocysteine-lowering therapy really has a role in the prevention of cardiovascular diseases. Large trials, which are already conducted, will probably give the definitive answer. In this review, we try to keep pace with the data that make the homocysteine hypothesis still doubtful.

Hyperhomocysteinemia is as a risk factor for increased vascular disease in l-dopa-treated Parkinson disease (PD) patients. This effect of l-dopa is associated with the metabolism of l-dopa by methylation. This study aimed to assess the effect of pergolide on plasma homocysteine levels. Plasma homocysteine levels were compared between PD patients treated with pergolide as monotherapy, with l-dopa as monotherapy, or with an l-dopa and pergolide combination and compared with controls. Plasma homocysteine levels were significantly higher in the l-dopa monotherapy group, and there were no significant differences for the pergolide treatment groups. Pergolide can be beneficial for increased plasma homocysteine levels.

See related article, pages 598–606 An elevated plasma level of homocysteine has long been known as an independent predictor of cardiovascular disease.1,2 However, in the absence of a clear mechanism linking homocysteine to cardiovascular disease, there has been an ongoing debate about whether this relationship is one of cause and effect or whether an elevated level of plasma homocysteine is an epiphenomenon, reflecting the presence of some other proatherogenic factor that is actually responsible for the cardiovascular disease. In the current issue of this journal, Liao et al3 suggest that the mechanistic link may be a homocysteine-induced reduction in the concentration of high density lipoproteins (HDLs). Liao et al3 report that homocysteine reduces the concentration of HDL cholesterol in plasma by inhibiting the hepatic synthesis of apoA-I, the main HDL apolipoprotein. This conclusion supports the findings from another recent study by Mikael et al4 who also reported that homocysteine inhibits apoA-I synthesis. The results of these 2 studies not only explain the documented inverse correlation between the plasma concentrations of HDL cholesterol and homocysteine5,6 but also raise the real possibility that a homocysteine-induced inhibition of apoA-I synthesis is the mechanism linking homocysteine to the development of atherosclerosis. A low concentration of HDL cholesterol has been shown in numerous human population studies to be highly predictive of premature cardiovascular disease.7,8 Furthermore, treatments that increase the level of HDL cholesterol in plasma in both animals9,10 and humans11,12 reduce the progression or even promote …

Plasma homocysteine levels increase in humans treated with fibrates but the molecular mechanisms are unknown. The goal of the present study was to determine the mechanism of this increase using animal models. Firstly, an increase in homocysteine was observed in mice treated with fenofibrate irrespective of the genetic background C57BL/6 or SV129. Secondly, as the effect of fenofibrate on gene expression is mediated through activation of the peroxisome proliferator-activated receptor alpha (PPARalpha), a transcription factor belonging to the nuclear receptor family, it was determined whether the effect of fenofibrate on homocysteine levels were modulated through PPARalpha activation. Using PPARalpha-deficient mice, it was shown that the homocysteine increase after fenofibrate treatment was completely abolished in these animals. It can be concluded that fibrates increase homocystinemia through a PPARalpha-mediated mechanism and that mice constitute an animal model for analyzing the molecular mechanisms behind the homocysteine increase after fibrate therapy in dyslipidemic patients.

In their study, Miller et al. separated both AD patients and controls into those with and without evidence of vascular disease and examined homocysteine levels. They found that elevated homocysteine was associated with patients (and controls) who had vascular disease but not specifically those diagnosed with AD. In contrast, low vitamin B6 status, which is seen with high homocysteine blood levels and which has been associated with poor memory in older adults was highly prevalent in the AD patients. The influence of homocysteine and B6 status on AD pathogenesis or progression remains to be determined. see page 1471 Sachdev et al. showed in their study of healthy elderly individuals that higher plasma homocysteine levels were related to brain atrophy as suggested by increased size of the lateral ventricles. see page 1539 Drazkowski …

The effects of nitrous oxide-induced cobalamin inactivation on homocysteine and folate metabolism have been investigated. Plasma levels of cobalamin, folate, homocysteine, and methionine were determined in 40 patients before and after operation under nitrous oxide anesthesia (range of exposure time, 70 to 720 minutes). Twelve patients anesthetized with total intravenous anesthesia served as control subjects (range of exposure time, 115 to 600 minutes). Postoperative plasma levels of folate and homocysteine increased (p < 0.001) up to 220% and 310%, respectively, in nitrous oxide-exposed patients, whereas plasma levels of methionine decreased (p < 0.025). Response occurred after 75 minutes of nitrous oxide exposure. The percentage increase of plasma folate and homocysteine correlated significantly with exposure time (p < 0.025 and p < 0.0001, respectively). In eight patients receiving nitrous oxide anesthesia plasma homocysteine levels had not returned to preoperative levels within 1 week (p < 0.01). Urinary excretion of folate and homocysteine increased during and after nitrous oxide exposure (p < 0.01 and p < 0.002, respectively) and correlated with exposure time (p < 0.01 and p < 0.005, respectively). It can be concluded that disturbance of homocysteine and folate metabolism by nitrous oxide develops with little delay and return to normal levels requires several days. Elevation of plasma homocysteine levels may therefore be used for monitoring nitrous oxide-induced cobalamin inactivation. Clinical Pharmacology and Therapeutics (1991) 49, 385–393; doi:10.1038/clpt.1991.45