Fasting Plasma Homocysteine Levels Research Articles

Relationship between MTHFR C677T, homocysteine, and ischemic stroke in a large sample of the Han Chinese population.

Ischemic stroke, one of the prevalent causes of death and disability worldwide, is linked to environmental and genetic factors, including polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) gene involved in homocysteine metabolism. The present study aimed to explore the relationship between the MTHFR C677T variant, plasma homocysteine, and risk of developing large-artery atherosclerotic ischemic stroke (LAAIS) among Han Chinese.A population-based case-control study, which included 1810 patients with LAAIS and 1765 unrelated control subjects, was conducted. Compared to the controls, LAAIS patients had a significantly higher prevalence of hypertension, diabetes mellitus, smoking, and alcohol consumption (P < .001), as well as significantly higher mean fasting blood glucose, triglyceride, total cholesterol, and plasma homocysteine levels (P < .001). The TT homozygous genotype correlated with increased risk of developing LAAIS, as indicated by a significantly higher odds ratio (OR) compared to the CT and CC genotypes, in both additive (OR = 3.215, P = .01) and recessive models (OR = 3.265, P = .01). The plasma homocysteine level was genotype-dependent according to the following trend: TT > CT > CC.In conclusion, our data demonstrate that, in spite of its low prevalence in both patients and controls (1.5% vs 0.8%), the MTHFR C677T variant could, at least in part, affect homocysteine levels and this, either alone or in combination with other factors, increases the risk of LAAIS.

Early supplementation of folate and vitamin B12 improves insulin resistance in intrauterine growth retardation rats.

Insulin sensitivity is changed during the neonatal period in small for gestational age (SGA) infants. Yet, the interventional strategies are still limited. We aimed to investigate the effects of supplementation with high folate and vitamin B12 diets in the early postnatal period on the changes in insulin sensitivity in an intrauterine growth retardation (IUGR) rat model. IUGR rat model was established by both low-protein diet feeding and daily diet restriction. High folate and vitamin B12 diet was supplied in IUGR as nutritional interventional group (IUGR-I), otherwise, the non-intervened IUGR group (IUGR-NI). In this study, male rats were studied in order to avoid hormonal and gender influence. At 21, 60 and 120 days, fasting plasma glucose, insulin, triglyceride, cholesterol, and homocysteine levels were measured among the control, IUGR-I, and IUGR-NI groups. Pearson analysis was used to evaluate the correlation between homocysteine and fasting blood glucose, insulin, HOMA-IR, triglyceride, and cholesterol levels. We established IUGR rat model by both low protein and restricted diet feeding during pregnancy and the incidence of IUGR pups was 93.33%. There was no difference in fasting glucose, insulin, HOMA-IR, triglyceride and cholesterol levels between the control, the IUGR-NI and the IUGR-I group at day 21. At day 60, insulin, HOMA-IR and triglyceride levels in the IUGR-I group were remarkably lower than those in the IUGR-NI group, but still higher than those in the control group (F=38.34, P=0.02; F=49.48, P=0.02; F=17.93, P<0.001, respectively). At day 120, glucose, insulin, HOMA-IR and Hcy levels in the IUGR-I group were obviously lower than those in the IUGR-NI group, although still higher than those in the control group (F=21.60, P<0.001; F=164.46, P<0.001; F=75.15, P<0.001; F=35.46, P<0.001, respectively). There were no significant differences in triglyceride and cholesterol levels between the IUGR-I group and the control group at day 120. At 120-day, homocysteine in IUGR-I group was highly positively correlated with fasting glucose and HOMA-IR (r=0.863, P=0.006; r=0.725, P=0.042, respectively); Only homocysteine was positively correlated with fasting glucose in IUGR-NI group (r=0.721, P=0.044). Early supplementation of folate and vitamin B12 improved insulin resistance and lipid levels in IUGR rats to some extent, along with decreasing homocysteine levels, but not enough to completely repair glucose and lipid metabolism.

Association Between Lipid Profiles and Arterial Stiffness in Chinese Patients With Hypertension: Insights From the CSPPT.

Arterial stiffness plays a key role in the pathogenesis of cardiovascular disease. However, the relationship between lipid levels and arterial stiffness is controversial. We aimed to investigate the association between lipid parameters and brachial-ankle pulse-wave velocity (baPWV) in Chinese patients with hypertension. A total of 14 071 participants with hypertension in the China Stroke Primary Prevention Trial (CSPPT) were enrolled in the present study. Patients were assigned to 4 equal groups according to their baPWV. Participants in the highest baPWV group were older with a higher prevalence of stroke and diabetes mellitus as well as higher body mass index (BMI), blood pressure, fasting plasma glucose, uric acid, total cholesterol (TC), triglycerides (TG), homocysteine (Hcy), and vitamin B12 levels ( P < .001). After adjusting for age, sex, BMI, and other cardiovascular risks, high-density lipoprotein cholesterol (HDL-C) was negatively related to baPWV (β = -0.22, P = .012), TC (β = 0.08, P = 0.001), TG (β = 0.14, P = .001); non-HDL-C (β = 0.12, P = .001) and positively related to baPWV. The effect was not observed for low-density lipoprotein cholesterol (LDL-C; β = 0.12, P = .335).These results suggested that non-HDL-C, TG, and TC were associated with arterial stiffness in a Chinese population with hypertension. HDL-C was inversely associated with arterial stiffness.

RANDOMISED DOUBLE-BLIND PLACEBO-CONTROLLED STUDY OF FOLIC ACID ADJUNCT FOR 8 WEEKS IN HYPERHOMOCYSTEINAEMIC HYPERTENSIVE PATIENTS IN ZARIA, NIGERIA

Objectives: This study was aimed at determining the effect of folic acid adjunct therapy on homocysteine (HCY) and blood pressure (BP) levels in hypertensive subjects.&#x0D; Method: The study was a double blind placebo-controlled trial on 100 hypertensive patients randomised into 50 folate and 50 placebo groups, where the folate group had 5 mg folic acid daily for 8 weeks. Fasting plasma homocysteine, folate and blood pressure levels were determined at baseline, at 4 and at 8 weeks. The Mixed Model Repeated Measures analysis of variance was applied for data analysis.&#x0D; Results: Hyperhomocysteinaemia was found at baseline in the folate (21.3 ± 5.7 µmol/L) and placebo (21.6 ± 4.9 µmol/L) groups which did not differ statistically (p &gt; 0.05). Folic acid adjunct therapy, reduced homocysteine levels at 4 weeks by 2.0 µmol/L (9.2 %, p &lt; 0.05) and at 8 weeks by 1.2 µmol/L (5.6 %, p &lt; 0.05), with no significant (p &gt; 0.05) systolic and diastolic blood pressure lowering effect. High base-line folate levels were found in both folate (113.8 ± 51.2 ng/ml) and placebo groups (109.5 ± 51.4 ng/ml) with no statistically significant difference (p &gt; 0.05).&#x0D; Conclusion: Short-term daily folic acid supplementation over 8 weeks had a significant homocysteine reduction effect with no significant reduction in systolic and diastolic blood pressures of hypertensive subjects in Zaria, Nigeria. Hyperhomocysteinaemia could not be accounted for by suboptimal folate levels.&#x0D; Keywords: Hypertension, Homocysteine, Blood pressure, Folate, Placebo, Nigeria.

Prevalence and clinical-demographic correlates of hyperhomocysteinemia in inpatients with bipolar disorder in a Han Chinese population

Recent studies have reported that hyperhomocystinemia (HHcy) is highly prevalent in patients with bipolar disorder (BD), placing them at greater risk of cardiovascular disease and possibly serving as a disease biomarker. However, the correlation of HHcy with demographic or clinical parameters is not well known. In this study, we examined the prevalence of HHcy and its association with these parameters in a sample of Chinese BD patients. Fasting plasma homocysteine (Hcy) levels were determined in 198 BD inpatients and 84 healthy controls. HHcy was defined when Hcy concentration exceeded 15.0µmol/L. Affective symptomatology was assessed by the Young Mania Rating Scale, Hamilton Depression Rating Scale and the Clinical Global Impressions severity scale. Compared to healthy controls, BD patients had a significantly higher prevalence (34.85% vs. 19.05%) of HHcy and a higher absolute level of homocysteine. Logistic regression analysis demonstrated that BD patients with HHcy were more likely to be male, have elevated BMI, more frequent treatment on lithium but less on valproate. These results suggest that Chinese inpatients with bipolar disorder have a higher rate of HHcy than the general population, and those at greatest risk are male, have an elevated BMI, and take more lithium but less valproate therapy.

Association study of methylenetetrahydrofolate reductase C677T mutation with cerebral venous thrombosis in an Iranian population.

There are limited data on the role of methylenetetrahydrofolate reductase C677T polymorphism and hyperhomocysteinemia as risk factors for cerebral venous thrombosis in Iranian population. We examined a possible association between fasting plasma homocysteine levels, methylenetetrahydrofolate reductase C677T polymorphism, and cerebral venous thrombosis in 50 patients with a diagnosis of cerebral venous thrombosis (20-63 years old) and 75 healthy controls (18-65 years old). Genotyping of the methylenetetrahydrofolate reductase C677T gene polymorphism was performed by PCR-restriction fragment length polymorphism analysis, and homocysteine levels were measured by enzyme immunoassay. Fasting plasma homocysteine levels were significantly higher in cerebral venous thrombosis patients than in controls (P = 0.015). Moreover, plasma homocysteine levels were significantly higher in methylenetetrahydrofolate reductase 677TT genotype compared to 677CT and 677CC genotypes in both cerebral venous thrombosis patients (P = 0.01) and controls (P = 0.03). Neither 677CT heterozygote genotype [odds ratio (OR) 1.35, 95% confidence interval (CI) 0.64-2.84, P = 0.556] nor 677TT homozygote genotype (OR 1.73, 95% CI 0.32-9.21, P = 0.833) was significantly associated with cerebral venous thrombosis. Additionally, no significant differences in the frequency of 677T allele between cerebral venous thrombosis patients and controls were identified (OR 1.31, 95% CI 0.69-2.50, P = 0.512). In conclusion, our study demonstrated that elevated plasma homocysteine levels are significant risk factors for cerebral venous thrombosis. Also, methylenetetrahydrofolate reductase 677TT genotype is not linked with cerebral venous thrombosis, but is a determinant of elevated plasma homocysteine levels.

Abstract P072: Short Sleep Duration is Associated with Elevated Homocysteine Levels

Introduction: Short and long sleep durations are associated with heightened risk for cardiovascular disease and vascular risk factors. Elevated homocysteine is also associated with greater risk for cardiovascular disease; however, studies have yet to investigate the relationship between sleep duration and homocysteine. Hypothesis: We hypothesized that short and long sleep duration would be associated with clinical levels of homocysteine. Methods: Adults (n=2,469; ≥20y) from the 2005-2006 National Health and Nutrition Examination Survey (NHANES) were assessed for habitual sleep duration (coded as &lt;5, 5, 6, 7, 8, 9, and ≥10hrs) and fasting plasma homocysteine levels (&lt;10 [normative], 10 to &lt;15 [pre-clinical] and ≥15 [clinical] μmol/L). Participants were excluded if pregnant, lactating, missing data on the primary variables, or if they had a history of cardiovascular disease, cancer, diabetes, kidney disease, or diagnosed sleep disorder. Population weighted, multinomial logistic regression analyses assessed the relationship between sleep duration and homocysteine after adjustment for age, sex, race/ethnicity, marital and menopausal status, shift work, dietary folate, alcohol intake, cotinine levels, reported physical activity, hypertension, and reported frequency of cessation of breathing at night. Results: Pre-clinical and clinical levels of homocysteine were present in 13.7% and 2.5% of the sample, respectively. The mean sleep duration was 6.9 ± 1.4 hours. In adjusted analyses, sleep duration was significantly related to homocysteine ( p &lt; 0.001). See Table. Very short sleepers (&lt;5hrs) were more likely to have clinical levels of homocysteine (OR: 3.01, 95%CI: 1.38, 6.57) compared to 7-hr sleepers. Conclusions: In a U.S. representative sample of adults without cardiovascular disease or other major conditions, short sleepers were at greater odds for clinical levels of homocysteine Findings suggest that homocysteine may be one mechanism linking short sleep duration to cardiovascular disease.

Association study of methylenetetrahydrofolate reductase A1298C mutation with cerebral venous thrombosis risk in an Iranian population.

Background:Cerebral venous thrombosis (CVT) is an uncommon condition characterized by severe clinical manifestations and high mortality rate. There is limited data on the role of methylenetetrahydrofolate reductase (MTHFR) A1298C mutation as a risk factor for CVT development in Iranians.Aim:The aim was to investigate a possible association between fasting plasma homocysteine (Hcy) levels, MTHFR A1298C mutation, and CVT in Iranian population.Materials and Methods:The study population consisted of 50 patients with a diagnosis of CVT (20–63 years old) and 75 healthy subjects (18–65 years old) as control. Genotyping of the MTHFR A1298C mutation and Hcy measurement was carried out by polymerase chain reaction-restriction fragment length polymorphism technique and enzyme immunoassay method, respectively.Results:Fasting plasma total Hcy levels were significantly higher in CVT patients than controls (P = 0.015). No significant differences were observed in the MTHFR A1298C genotypes frequency between CVT patients and controls (P > 0.05). The frequency of the 1298C allele was 36% and 37.5% in CVT patients and controls, respectively and did not differ significantly between the two groups (P = 0.16).Conclusions:Our study demonstrated that MTHFR A1298Cmutation is not a significant risk factor for CVT.

Association of seven functional polymorphisms of one-carbon metabolic pathway with total plasma homocysteine levels and susceptibility to Parkinson's disease among South Indians

This study from South India was performed to ascertain the impact of seven functional polymorphisms of one-carbon metabolic pathway on total plasma homocysteine levels and susceptibility to PD. A total of 151 cases of Parkinson's disease and 416 healthy controls were analyzed for fasting plasma homocysteine levels by reverse phase HPLC. PCR-RFLP approaches were used to analyze glutamate carboxypeptidase II (GCPII) 1561 C>T, reduced folate carrier 1 (RFC1) 80 G>A, cytosolic serine hydroxymethyl transferase (cSHMT) 1420 C>T, methylene tetrahydrofolate reductase (MTHFR) 677 C>T, methionine synthase (MTR) 2756 A>G and methionine synthase reductase (MTRR) 66 A>G polymorphisms. PCR-AFLP was used for the analysis of thymidylate synthase (TYMS) 5′-UTR 28bp tandem repeat. PD cases exhibited elevated plasma homocysteine levels compared to controls (men: 28.8±6.9 vs. 16.4±8.8μmol/L; women: 25.4±5.3 vs. 11.2±5.1μmol/L). Homocysteine levels showed positive correlation with male gender (r=0.39, p<0.0001) and MTRR 66 A>G (r=0.31, p<0.0001) whereas an inverse correlation was observed with cSHMT 1420 C>T polymorphism. MTRR 66 A>G polymorphism showed independent risk for PD (OR: 3.42, 95% CI: 2.35–4.98) whereas cSHMT 1420 C>T conferred protection against PD (OR: 0.11, 95% CI: 0.07–0.17). Multifactor dimensionality reduction analysis showed synergistic interactions between MTHFR 677 C>T and MTRR 66 A>G, whereas cSHMT 1420 C>T exhibited counteracting interactions in altering susceptibility to PD. To conclude, PD cases exhibited hyperhomocysteinemia and MTRR 66 A>G and cSHMT 1420 C>T gene variants were shown to modulate PD risk by altering the homocysteine levels.

Inherited and Secondary Thrombophilia

Case Presentation 1: A healthy 19-year-old man presented with new chest pain and near syncope. Computed tomography pulmonary angiography showed a saddle pulmonary embolus. The patient denied recent travel, trauma, surgery, or hospitalization. His mother had 2 miscarriages at 10 weeks of gestation, and his maternal grandfather had deep venous thrombosis at 60 years of age. Case Presentation 2: A healthy 45-year-old woman reported new dyspnea and left calf pain. Computed tomography pulmonary angiography and compression venous duplex ultrasonography showed bilateral pulmonary emboli and acute left leg deep vein thrombosis, respectively. The patient denied exogenous hormone use, recent travel, trauma, surgery, or hospitalization. Her health maintenance was current, and she gave a family history of pernicious anemia, Grave disease, and amyotrophic lateral sclerosis. Laboratory analyses showed reduced hemoglobin (11.4 g/dL; normal, 12.0–15.5 g/dL), increased red blood cell distribution width (18.9%; normal, 11.9%–15.5%), and mild thrombocytopenia. Neither patient had previous venous thromboembolism, and both were referred to the Mayo Clinic Thrombophilia Center for apparent idiopathic venous thromboembolism. Thrombophilia is defined as a predisposition (susceptibility) to thrombosis. Thrombophilia is not a disease per se, but may be associated with a disease (eg, cancer), drug exposure (eg, oral contraceptives) or condition (eg, pregnancy or postpartum, secondary thrombophilia; Table 1), and thrombophilia may be inherited (Table 2).1 This concept is important because disease susceptibility does not imply an absolute requirement for primary or secondary prevention, or for treatment. Most persons with a thrombophilia do not develop thrombosis. Thus, thrombophilia must be considered in the context of other risk factors for incident thrombosis, or predictors of recurrent thrombosis, when estimating the need for primary or secondary prophylaxis, respectively. View this table: Table 1. Secondary Thrombophilia1 View this table: Table 2. Inherited Thrombophilia1 The role of special coagulation testing for an acquired or inherited thrombophilia is controversial. Thrombophilia testing should only be done if …

Association of methylenetetrahydrofolate reductase C677T and A1298C polymorphisms with myocardial infarction in Tunisian young patients

Myocardial infarction (MI) is an important clinical problem because of its large contribution to mortality. The objective of this study is to assess whether two methylenetetrahydrofolate reductase (MTHFR) polymorphisms, C677T and A1298C, were associated with MI among Tunisian patients. One hundred young patients (<47 years old) with MI were recruited and compared with 200 control subjects with no history of MI. The most common MI risk factors were investigated. Fasting plasma homocysteine levels were measured. Genotypes of the MTHFR C677T and A1298 polymorphisms were studied by polymerase chain reaction. The mean plasma homocysteine level in the study group was raised when compared with the control group. Homozygous MTHFR C677T mutation was observed in 2 (2 %) patients and in 17 (8.5 %) control subjects, whereas heterozygous MTHFR C677T mutation was detected in 82 (82 %) patients versus only 79 (39.5 %) in control subjects. The mean total homocysteine concentrations were significantly higher in individuals with the 677TT and CT genotypes. Our results indicate that C677T and A1298C MTHFR mutations and hyperhomocysteinemia contributed to the risk factors for MI.

Racial-ethnic differences in stroke risk factors and subtypes: results of a prospective hospital-based registry

A majority of stroke research in the United States focuses on Caucasian and African-American populations, limiting the amount of comparative stroke data available on other racial and ethnic groups. The purpose of this research was to examine differences in stroke risk factors/subtypes between minority stroke patient groups in the United States (Asian-Indian, African-American, and Hispanic), using a Caucasian reference group. All patients had a comprehensive stroke work-up to ascertain their stroke risk factors and their stroke etiology applying TOAST criteria. Minority groups were younger compared with the white stroke patients, with the mean age significantly lower in the Asian-Indian and the Hispanic groups. The male:female ratio favored males in the Asian-Indian and Hispanic subgroups and females in the Caucasian and African-American groups. Diabetes was more prevalent in the minority subgroups, with a highest prevalence (55%) noted in the Asian-Indian group. The minority groups had lower prevalence of atrial fibrillation, carotid stenosis (≥70%), CAD, PVD, smoking, and alcohol use. The Asian-Indian stroke group had a higher median fasting plasma homocysteine level compared with the reference white group (12.1 vs. 10.4, p = 0.002). Compared to the reference white stroke group, the Asian-Indian stroke group had fewer strokes related to cardioembolism (7% vs. 25%) and a higher number of strokes related to small vessel occlusive disease (25% vs. 11%). There are some similarities in the stroke risk factors between the minority stroke groups, but the data indicate that there are different trends in stroke risk factors and subtypes.

Hyperhomocysteinemia as a Risk Factor for IUGR

To study the role of hyperhomocysteinemia in patients with intrauterine growth retardation. 76 patients with intrauterine growth retardation were studied and compared with 50 controls which included pregnant patients without any pregnancy complications. Fasting Plasma homocysteine levels were measured and statistical analysis using tests of significance and logistic regression analysis was performed. Those in the study group were given homocysteine lowering agents for 6 wks and pregnancy outcome was studied. 57.8% women in the study group were found to have hyperhomocysteinemia. Logistic Regression analysis shows an OR of 2.45 in favor of occurrence of IUGR if homocysteine levels are raised which is statistically significant. Mean plasma homocysteine levels decreased after treatment for 6 wks but this decrease in the case of placebo group is marginal whereas the decrease in the homocysteine levels the treatment group. This implies that treatment has a definitive role in lowering of plasma homocysteine levels. The present study shows that hyperhomocysteinemia is associated with IUGR and should be identified as a risk factor as correction favors pregnancy outcome.

Abstract 2661: Unique Attributes Of Asian-Indian Stroke/Transient Ischemic Attack (TIA) Patients: Results of a Prospective Multi-ethnic Hospital-based Registry

Introduction: The New Jersey Neuroscience Institute (NJNSI) serves the Middlesex County, NJ which, has a population of 750,000 (68.4% white, 7.3% Asian-Indian, 9.1% African-American, 15.2% others; 13.6% Hispanic of any race, based on 2000 US Census). This prospective multi-ethnic hospital-based registry provides a unique opportunity to study Asian-Indian stroke/TIA patients. Hypothesis: There are differences of stroke risk factors/subtypes between Asian-Indian and Caucasian stroke/TIA patient groups, in light of similar differences noted in the African-American and Hispanic groups individually in relation to the Caucasian group. Methods: Between 1998 and 2009, data on stroke risk factors and stroke subtypes were collected on 1100 consecutive stroke/TIA patients (1037 or 94.3% non-Hispanic; 63 or 5.7% Hispanic) admitted to the NJNSI. Of the non-Hispanics, 768 (74.1%) were Caucasian, 99 (9.6%) Asian-Indian, 139 (13.4%) African-American, 31 (3.0%) were others. Stroke risk factors assessed included age, gender, hypertension, diabetes, atrial fibrillation evaluated by 48-hour Holter monitor, hyperlipidemia evaluated by fasting lipid profile, prevalent coronary artery disease, smoking history, alcohol use, carotid stenosis (&gt;70%) evaluated by duplex ultrasound, fasting homocysteine level and stroke subtypes (using TOAST classification). Asian-Indians, African-American and Hispanic groups were individually compared with the Caucasian group (control) in this study using odds ratio (OR) analyses and X2 test for categorical variables and t-test for continuous variables. Results: The Asian-Indian group was younger (66±12 vs 72±14, p &lt;0.001), higher proportion of males (OR 2.1, p=0.001) and diabetes (OR 2.3, p&lt; 0.001); lower proportion of atrial fibrillation (OR 0.2, p&lt;0.001), smokers (OR 0.3, p&lt;0.001), Alcohol users (OR 0.4, p=0.003) and higher fasting plasma homocysteine level (17.2±20.3 vs 11.9±7.4, p=0.002). There were fewer strokes related to cardioembolism (OR 0.2, p&lt;0.0001) and a higher number of strokes related to small vessel occlusive disease (OR 2.4, p = 0.001). The African-American group had lower proportion of carotid stenosis (OR 0.5, p=0.007) and atrial fibrillation (OR 0.6, p=0.034). African-American group had higher levels of fasting triglyceride level (Median 92 vs 122 mg/dL). The Hispanic group resembled the Asian-Indian group in that they were younger (64±16 vs 72±14, p&lt; 0.001), had a higher proportion of diabetes (OR 1.7, p=0.039), lower proportion of atrial fibrillation (OR 0.5, p=0.037) than the Caucasian group. Conclusions: The Asian-Indian stroke/TIA group in this community has unique attributes in respect to stroke risk factors and stroke subtype. There are few similarities in the stroke risk factors with the Hispanic stroke/TIA group.

Associations among objectively measured physical activity, fasting plasma homocysteine concentration, and MTHFR C677T genotype

Elevated fasting plasma homocysteine (Hcy) level is a vascular disease risk factor. Plasma Hcy is affected by 5,10-methylenetetrahydofolate reductase (MTHFR) genotype and dietary folate intake. This cross-sectional study in 434 Japanese adults examined the associations among objectively measured physical activity (PA), plasma Hcy adjusting for dietary folate intake, and MTHFR C677T genotype. Daily PA was measured by triaxial accelerometry and all subjects completed a questionnaire about their dietary habits. Plasma Hcy and MTHFR C677T genotype were determined. Plasma Hcy in subjects with the TT genotype was significantly higher than in those with CC or CT genotype (p < 0.001). Plasma Hcy was significantly different between ≥ 200 (7.6 ± 0.2 nmol/mL) and <200 µg/day (8.3 ± 0.3 nmol/mL) folate intake groups (p = 0.003). There were no differences in plasma Hcy adjusting for age, sex, and folate intake between groups according to PA category in all subjects. However, there were significant interactions between time spent in light PA (p = 0.003), vigorous PA (p = 0.001), or inactivity (p = 0.004), and MTHFR genotype. In only the TT genotype, shorter time spent in light PA was associated with higher plasma Hcy than a longer time spent in light PA (11.5 ± 3.3 nmol/mL vs. 8.5 ± 3.3 nmol/mL, p < 0.001), and longer time spent in vigorous PA and inactivity were associated with higher plasma Hcy (11.8 ± 3.3 nmol/mL vs. 8.4 ± 3.2 nmol/mL, 11.6 ± 3.3 nmol/mL vs. 8.4 ± 3.3 nmol/mL, respectively, p < 0.001). In conclusion, light and vigorous PA were associated with plasma Hcy only in the TT genotype, but there were no such associations in all genotypes.

Nutrigenetic impact of daily folate intake on plasma homocysteine and folate levels in patients with different methylenetetrahydrofolate reductase genotypes

Elevated plasma homocysteine level is associated with coronary artery disease (CAD). Homozygosity for the C677T mutation in the methylenetetrahydrofolate reductase (MTHFR) gene is typically but inconsistently associated with hyperhomocysteinemia. We examined the impact of daily intake of folate, a co-factor in homocysteine metabolism, on plasma homocysteine and folate levels in CAD patients in relation with MTHFR genotypes. Daily folate intake was assessed from 3-day food records in 99 patients with CAD: 35 with the T/T (homozygous mutant) genotype and 64 with the C/C or C/T (non-T/T) genotypes. Patients with the T/T genotype had higher fasting plasma homocysteine levels (18.4±1.9 vs. 12.6±0.6 μmol/l, P=0.01) and lower plasma folate levels (17.8±1.7 vs. 20.8±1.0 nmol/l, P=0.02). There were no differences between the genotype groups in energy-adjusted folate intake. In patients with the non-T/T genotypes, higher folate intake was associated with higher plasma folate levels and lower plasma homocysteine levels. In T/T homozygotes this association was weaker. Linear regression analysis showed that folate intake, the MTHFR genotype, plasma vitamin B12 levels, and the interaction between plasma folate level and MTHFR genotype, predicted homocysteine elevation. (folate intake, P=0.04, MTHFR genotype, P=0.03, plasma folate, P=0.02, and plasma B12 level, P=0.004). The model explained only 29% of the variance in log-transformed plasma homocysteine levels. T/T homozygotes are more sensitive to the combination of low folate intake, low plasma folate and vitamin B12 level, than patients with non-T/T genotypes. The variability in plasma homocysteine in T/T homozygotes is only partly explained by these variables.

Effect of Highly Active Antiretroviral Therapy on Homocysteine Plasma Concentrations in HIV-1–Infected Patients

To analyze the effect of antiretroviral therapy on homocysteine levels in HIV-1-infected patients. Observational, prospective study of patients with AIDS. We included patients with HIV-1 infection naive for antiretroviral drugs. Before and after 6 months of treatment, we evaluated fasting and postoral methionine load plasma homocysteine, serum vitamins B6 and B12, and intraerythrocyte folate levels. We studied 69 patients who began therapy for a 6-month period. Fasting and postoral methionine load plasma homocysteine levels increased significantly after 6 months of antiretroviral therapy with respect to basal values (P < 0.001). Fasting hyperhomocysteinemia was present in 7.3% of patients before treatment and in 89.9% after 6 months of therapy (P = 0.0001). Postoral methionine load hyperhomocysteinemia was found in 4.5% of subjects before therapy vs. 98.5% at the end of study period (P = 0.001). These results were not associated with folate or vitamins B6 or B12 levels. In patients with HIV-1 infection, fasting and postoral methionine load plasma homocysteine levels increased after 6 months of antiretroviral treatment. Nutritional abnormalities were not responsible for hyperhomocysteinemia, suggesting that enzymatic disturbances in the metabolic pathways of homocysteine may occur.

Endothelial nitric oxide synthase gene polymorphisms and the risk of silent brain infarction

Silent brain infarction (SBI), a unique cerebrovascular disorder, is frequently detected on magnetic resonance imaging (MRI) of apparently healthy elderly persons, and it is known to increase the risk of stroke and other related diseases. Although detailed mechanisms of SBI pathogenesis have yet to be determined, recent studies suggest that SBI is significantly influenced by genetic factors. In this study, we investigated polymorphisms in the endothelial nitric oxide synthase (eNOS) gene (i.e., -786T>C, 4a4b and 894G>T) as possible risk factors for SBI. We enrolled 269 patients with SBI and 234 control subjects and examined their fasting plasma homocysteine and folate levels, and analyzed for eNOS polymorphisms and haplotypes. The prevalence of SBI was shown to be significantly higher in patients with the eNOS 894GT genotype (OR, 2.00; 95% CI, 1.30-3.08) and 894GT+TT genotype (OR, 2.05; 95% CI, 1.34-3.16), compared with the 894GG genotype. However, in the case of -786T>C and 4a4b polymorphisms, no significant difference was observed between SBI patients and normal subjects. Interestingly, we found that the prevalence of SBI can increase twice as high when either -786T>C or 4a4b polymorphism was combined with 894G>T polymorphism, -786TC+CC/894GT+TT (OR, 3.83; 95% CI, 1.24-11.80) and 4a4b+4a4a/894GT+TT (OR, 4.08; 95% CI, 1.34-12.40), respectively. According to haplotype analysis, we found that three haplotypes (-786T-4b-894G, -786T-4b-894T and -786C-4a-894T) were shown to be significantly different between SBI patients and control subjects. These results indicate that eNOS polymorphisms and haplotypes serve as risk factors for SBI, and three different polymorphic loci in the eNOS gene play interactively, thereby leading to synergistic effects for the generation of SBI.

Effect of B vitamin supplementation on plasma homocysteine levels in celiac disease

To investigate the effect of vitamin supplements on homocysteine levels in patients with celiac disease. Vitamin B6, folate, vitamin B12, and fasting plasma homocysteine levels were measured in 51 consecutive adults with celiac disease [median (range) age 56 (18-63) years; 40% men, 26 (51%) had villous atrophy, and 25 (49%) used B-vitamin supplements] and 50 healthy control individuals matched for age and sex. Finally, the C677T polymorphism of 5,10-methylenetetrahydrofolate reductase (MTHFR) was evaluated in 46 patients with celiac disease and all control individuals. Patients with celiac disease and using vitamin supplements had higher serum vitamin B6 (P = 0.003), folate (P < 0.001), and vitamin B12 (P = 0.012) levels than patients who did not or healthy controls (P = 0.035, P < 0.001, P = 0.007, for vitamin B6, folate, and vitamin B12, respectively). Lower plasma homocysteine levels were found in patients using vitamin supplements than in patients who did not (P = 0.001) or healthy controls (P = 0.003). However, vitamin B6 and folate, not vitamin B12, were significantly and independently associated with homocysteine levels. Twenty-four (48%) of 50 controls and 23 (50%) of 46 patients with celiac disease carried the MTHFR thermolabile variant T-allele (P = 0.89). Homocysteine levels are dependent on Marsh classification and the regular use of B-vitamin supplements is effective in reduction of homocysteine levels in patients with celiac disease and should be considered in disease management.

Effect of Zinc Supplementation on Serum Homocysteine in Type 2 Diabetic Patients with Microalbuminuria

Elevated homocysteine levels are considered to be an independent risk factor for cardiovascular complications in diabetic patients. The aim of this study was to find out if zinc supplementation improves homocysteine levels, which may exert vascular-protective effects in type 2 diabetes subjects with microalbuminuria. In a randomized, double-blind, controlled, crossover study, 50 type 2 diabetic patients with microalbuminuria were subdivided into two groups and supplemented with 30 mg/d of zinc (group 1) or placebo (group 2) for three months with a four-week wash out period. Serum creatinine, vitamin B(12), folate, fasting plasma glucose, HbA1c, lipid profiles, zinc, homocysteine levels and random urine albumin were measured before and after the first and second phase of the study in all participants. Mean serum zinc was significantly increased after zinc supplementation (from 76 +/- 16 mug/dl to 93 +/- 20 microg/dl; p < 0.05), while there was no change in the placebo group (75 +/- 16 microg/dl to 75 +/- 15 microg/dl). With zinc supplementation, homocysteine levels reduced significantly (from 13.71 +/- 3.84 mumol/l to 11.79 +/- 3.06 mumol/l; p < 0.05), which did not occur on placebo (from 12.59 +/- 2.13 mumol/l to 13.36 +/- 2.03 mumol/l). Simple regression was used to show a positive correlation between urine albumin excretion and serum homocysteine (r = 0.37, p = 0.023). Vitamin B(12) and folate levels increased significantly in patients who received zinc in comparison to those who received placebo. A negative correlation was observed between homocysteine and vitamin B(12) concentration (r = -0.36, p = 0.025). Zinc supplementation reduced serum homocysteine and increased vitamin B(12) and folate concentrations in type 2 diabetic patients with microalbuminuria.