tHcy Concentrations Research Articles

Serum folate, total homocysteine levels and methylenetetrahydrofolate reductase 677C>T polymorphism in young healthy female Japanese.

Environmental and genetic factors influence serum total homocysteine (tHcy), a risk factor for vascular diseases. The gene polymorphism of methylenetetrahydrofolate reductase (MTHFR) is reported to be a genetic factor for influencing tHcy. However, it is not clear whether MTHFR polymorphism influences tHcy in the younger generation. To investigate the influence of MTHFR polymorphism on vascular disease risks in young Japanese females, we determined dietary intakes, serum folate and tHcy, and examined the influence of MTHFR 677C>T polymorphism in healthy junior and high school students (n=192, 12-18y). The relationships between MTHFR polymorphism and folate intake, serum folate or tHcy were investigated by dividing participants into CC, CT and TT types. Among individuals with the TT genotype, folate and tHcy levels were significantly lower (p<0.05) or higher (p<0.0001), respectively, than in those with the other genotypes; although there were no significant differences in the intake of folate among genotypes. In addition, a significant inverse correlation between folate and tHcy (p<0.05) was noted in all genotypes, even in young females, so far not examined in Asian populations. Therefore, MTHFR genotypes were proven to be a significant determinant for folate and tHcy concentrations. However, the association of increased folate intake with lower tHcy concentration, even in cases of the mutation TT type, indicates the importance of folate intake in young Japanese females for early detection of risk, as well as the prevention of vascular diseases.

Association between endothelial nitric oxide gene intron 4a4b VNTR polymorphism and plasma homocysteine concentrations in Tunisian male patients with myocardial infarction

Many studies have shown that hyperhomocysteinemia may be an independent risk factor for coronary artery disease. However, not all prospective studies support an association between elevated plasma homocysteine levels and coronary artery disease. Nitric oxide (NO) plays a relevant role in various events during atherogenesis, and in vitro data suggest that NO may modulate total homocysteine (tHcy) concentrations, whereas polymorphisms of the endothelial nitric oxide (NOS3) gene have been reported to be related to an increased risk of myocardial infarction (MI) and hyperhomocysteinemia, but the results have been controversial. We hypothesized that the NOS3 synthase 4a4b VNTR polymorphism is a determinant of tHcy concentrations and tested this in 310 patients with MI and 250 controls. The NOS3 gene intron 4a4b VNTR polymorphism was analyzed by polymerase chain reaction analysis. There was no significant difference in the homocysteine levels between patients with MI and controls. The frequencies of the NOS34b4b, 4b4a, and 4a4a genotypes in the MI group were significantly different from those in the control group. In patients with MI, plasma tHcy concentrations were significantly different among the NOS3 genotypes (13.5±4.5, 18.5±3.9, and 20.4±2.1 μmol/L for 4b4b, 4a4b, and 4a4a genotypes, respectively; P<.001). However, no significant difference was observed for tHcy concentrations in the control group. In conclusion, the NOS34a4b gene polymorphism (presence of 4a allele) is associated with MI and influences plasma tHcy concentrations in patients with MI in the Tunisian male population.

Antioxidant Defense of Betaine Against Oxidative Stress Induced by Ethanol in the Rat Testes

Oxidative stress is one of the factors associated with decline in fertility and betaine has been shown to bear antioxidant and methyl donor properties in our recent studies. Thus, we designed the present study to examine antioxidant and methyl donor abilities of betaine in oxidative stress induced by ethanol in the rat testes. The adult male Sprague-Dawley rats were divided into four experimental groups and treated daily for 2 months as follows: control, ethanol (4 g/kg, orally), betaine (1.5 % of total diet, orally), and betaine plus ethanol (betaine, 1.5 % of total diet and after 120 min, ethanol 4 g/kg). Sperm motility and concentration significantly increased in betaine group when compared to the ethanol–treated rats. The main antioxidant enzyme (GPx) activity significantly increased (in order compensatory) in ethanol-treated rats when compared to betaine group while, antiperoxidative enzyme (CAT) activity significantly increased in betaine plus ethanol group as compared to ethanol-treated rats. Total homocysteine (tHcy) and TBARS concentration (as a lipid peroxidation marker) also significantly decreased in betaine and betaine plus ethanol groups as compared to ethanol-treated rats. Overall, methyl donor and antioxidant properties of betaine are promising and reduce the elevated tHcy and TBARS concentrations in betaine plus ethanol group. Therefore, betaine might be used as a potential therapy in hyperhomocysteinemia and oxidative stress induced by ethanol in alcoholism.

Role of folic acid depletion on homocysteine serum level in children and adolescents with epilepsy and different MTHFR C677T genotypes

Homocysteine (Hcy) is a sulfur-containing amino acid involved in methionine metabolism. An elevated total plasma Hcy concentration (tHcy) is a risk factor for vascular disease. The present study aimed to assess the role of antiepileptic drugs (AEDs) and C677T methylenetetrahydrofolate (MTHFR) polymorphisms on tHcy in pediatric patients with epilepsy treated for at least 6 months with various treatment regimens protocols including the newer AEDs.The study group was recruited from children and adolescents with epilepsy followed up in the Child Neuropsychiatry Clinic of the Second University of Naples, between January 2007 and March 2008. Inclusion criteria were: (1) patients with epilepsy, treated with one or more anticonvulsant drugs for at least 6 months; (2) age between 2 and 16 years. Plasma tHcy concentrations were considered elevated when they exceeded 10.4μmol/L, and folate concentrations <3ng/mL were considered deficient. Serum vitamin B12 levels were considered normal between 230 and 1200pg/mL. The study group was composed of 78 patients (35 males, 43 females), aged between 3 and 15 years (mean 8.9 years). Thirty-five patients were taking AED monotherapy, 43 polytherapy. Sixty-three healthy sex- and age-matched children and adolescents served as controls. The mean tHcy value in the patient group was higher than the mean value in the control group (12.11±7.68μmol/L vs 7.4±4.01μmol/L; p<0.01).DNA analysis for the MTHFR C677T polymorphism showed the CT genotype in 46%, CC in 35% and TT in 17.8% of cases. Decreased folic acid serum levels significantly correlated with increased tHcy levels (p<0.003). Female sex was a less significant risk factor for increased tHcy levels (p=0.039).Our study confirms the association between hyperhomocysteinemia and epilepsy. The elevation of tHcy is essentially related to low folate levels. Correction of poor folate status, through supplementation, remains the most effective approach to normalize tHcy levels in patients on AED mono- or polytherapy.

Nutritional Factors, Homocysteine and C677T Polymorphism of the Methylenetetrahydrofolate Reductase Gene in Algerian Subjects with Cardiovascular Disease

Abstract The C677T variant of methylenetetrahydrofolate reductase (MTHFR), a key enzyme in the remethylation of homocysteine (HCY) to methionine, is a frequent genetic cause of moderate hyperhomocysteinemia (HHCY) among individuals with cardiovascular disease (CVD), and particularly when combined with other factors such as hyperlipidaemia. However, in Algeria the influence of nutrient-gene interactions is not known. The aim of the present study was to explore the influence of age and gender, together with folate status, on the association between the C677T MTHFR polymorphism and plasma total HCY (tHCY) concentrations. This research was carried out as a prospective study on 98 patients hospitalized in the Cardiology Section, University of Sétif, Algeria. Mean age of participants was 57 y (range 20-96 y).The genetic analysis of the MTHFR C677T polymorphism was performed by real-time polymerase chain reaction (PCR) performed on Light Cycler in borosilicate capillaries with MTHFR 677CT polymorphism detection kit. The concentrations of tHCY, folic acid vitamin B12 levels were determined using a competitive immunoassay on the IMMULITE 1000 Analyzers. Plasma total cholesterol, triglycerides, glucose, creatinine and urea concentrations were measured by colorimetric methods. Assays were conducted according to the manufacturers' instructions. Plasma tHCY was significantly higher in the patients with CVD, and HHCY was associated with the presence of mildly elevated serum urea and creatinine (p &lt;0.05). MTHFR gene mutation does not seem to be associated with elevation of plasma tHCY in the studied patients and this lack of correlation could be influenced by the higher folate concentrations in our study. CVD patients with 677CT/TT genotypes had a higher concentration of total cholesterol than those with 677CC genotype (p &lt;0.05). Although, the presence of 677T variant together with hypofolatemia (&lt;15.4 ng/ml) had a more detrimental effect on the level of total cholesterol (p &lt;0.05). Folatemia and vitamin B12 were much higher in 677CC genotype compared to 677CT/TT genotype in CVD subjects without hyperlipidemia (p &lt;0.05). However in patients with hyperlipidemia these values became lower also with 677CC genotype. In conclusion, hyperlipidemia affects the levels of plasma folate and vitamin B12 concentrations independent of mutated MTHFR genotype. The effect of 677T variant on total cholesterol, folate and vitamin B12 concentrations may relate to possible adverse effects of elevated tHCY on lipid profiles and on plasma folate and vitamin B12.

Influence of Retinopathy on Plasma Concentrations of total Homocysteine and other Biochemical Parameters in Algerian Patients with Type 2 Diabetes Mellitus

Abstract Homocysteine (HCY) has been identified as a risk factor for vascular disease in the general population. Diabetic retinopathy (DR) itself rather than hyperhomocysteinemia is the leading cause of blindness among patients with type 2 diabetes mellitus (T2DM). Our study was conducted with 60 healthy control subjects and 178 subjects with T2DM. They were enrolled in the Diabetes Prevention Program from September 2007 to December 2008. Of the 178 patients, 121 cases (68%) had DR Mean plasma total HCY (tHCY) levels were found to be higher in T2DM patients compared to controls (p &lt;0.001), and were also higher than that of the DR group (p &lt;0.001). Plasma folic acid levels were lower in the DR group compared with T2DM without DR and the control group (p &lt;0.001), but there were no significant differences between the latter and the controls. Moderate hyperhomocysteinemia was significantly associated with lower vitamin B12 and folic acid concentrations and older age. Concentrations of serum total cholesterol, LDL-cholesterol (LDL-C), and triglycerides (TG) were significantly raised (p &lt;0.001) whereas the level of HDL-cholesterol (HDL-C) was decreased (p &lt;0.001) in diabetic subjects as compared to controls. Logistic regression analysis showed that DR after adjustment was significantly associated with the following factors: cholesterol, HDL-C and TG. The analysis in DR patients after controlling for cholesterol and TG was independent of plasma tHCY concentrations (OR = 28.5 and OR = 11.9; respectively). In conclusion, results suggest a possible association between moderate hyperhomocysteinemia, traditional risk factors and folic acid deficiency could be an independent risk factor for DR.

Maternal homocysteine and small-for-gestational-age offspring: systematic review and meta-analysis

Growth retardation in utero leading to small-for-gestational-age (SGA) newborns is associated with increased neonatal morbidity and mortality and with lifelong consequences such as poor cognitive function and cardiovascular diseases. Maternal total homocysteine (tHcy) concentrations have been linked to a wide range of adverse pregnancy outcomes and could possibly influence birth weight. We performed a systematic review of and meta-analysis on the association of maternal tHcy and birth weight. A literature search of English, German, and French publications with the use of the PubMed database (January 1966-July 2010) found 78 abstracts. Search terms were as follows: homocysteine AND (birth weight OR small for gestational age OR intrauterine growth retardation). Studies were eligible if information on maternal tHcy and birth weight and the possible association between maternal tHcy and birth weight was available. Effect size estimates were converted to ORs as estimates of the RR of a woman to deliver SGA offspring when maternal tHcy exceeded the 90th percentile. The search yielded 19 studies for analysis, consisting of 21,326 individuals. Pooled analysis resulted in a crude OR of 1.25 (95% CI: 1.09, 1.44). When this estimate was expressed as a linear effect, it corresponded to a decrease in birth weight of 31 g (95% CI: -13, -51 g) for a 1-SD increase in maternal tHcy. Higher maternal tHcy concentrations are associated with a small increased risk for SGA offspring. The small estimated birth weight difference might be of little clinical relevance for the individual newborn; however, it could be of greater importance at a population level.

Lipoprotein(a) and Homocysteine Potentiate the Risk of Coronary Artery Disease in Male Subjects

Lipoprotein (Lp(a)) and homocysteine (Hcy) are independent risk factors for coronary artery disease (CAD). Hcy promotes the release of free apo(a) from Lp(a). The high fibrin affinity of free apo(a) inhibits plasminogen binding and plasmin generation. Hyperhomocysteinemia can result from a less active variant of methylene tetrahydrofolate reductase (variant C677T). Because the C677T genotype is estimated to be present in 32.2% of the Mexican population, we took advantage of this prevalence to determine the possible potentiating effect between high plasma Lp(a) and Hcy for increasing the risk of CAD in male patients. First, 222 male patients admitted for coronary angiography were recruited and classified as CAD+ or CAD-. Anthropometric measurements, traditional risk factors, and plasma total Hcy (tHcy) and Lp(a) levels were recorded in both groups. We performed a conditional logistic regression model adjusted for conventional risk factors of CAD and it became clear that Lp(a) ≥30mg/dl was a risk factor for CAD (odds ratio [OR] 5.06, 95% confidence interval [CI] 1.88-13.51, P=0.001), whereas Hcy was not related to CAD (OR 0.44, 95% CI 0.63-2.90, P=0.44). However, when both factors were considered together in an interaction model, high tHcy and high Lp(a) plasma concentrations showed a potentiated effect (OR 10.52, 95% CI 2.18-50.71, P=0.003). The combination of high Lp(a) and Hcy levels synergistically increases the likelihood of developing CAD in male patients.

Homocysteine: An Emerging Cardiovascular Risk Factor that Never Really Made it~!2009-10-29~!2009-12-27~!2010-04-08~!

Serum total homocysteine (tHcy) has been implicated in promoting venous thromboembolic events and athero- sclerosis, manifested as coronary heart disease, stroke or peripheral arterial disease. Dietary supplementation with B vita- mins that lower tHcy concentrations was expected to reduce cardiovascular disease (CVD) risk. However, recent meta- analyses of prospective observational studies and randomized controlled trials failed to show a role of tHcy in the patho- genesis of vascular disease or a benefit of B vitamins in CVD events. This review analyzes recent data on the potential of tHcy to cause health problems (if any) and the role of vitamin B supplementation in preventing them.

Choline supplementation and measures of choline and betaine status: a randomised, controlled trial in postmenopausal women

Choline is an essential nutrient and can also be obtained by de novo synthesis via an oestrogen responsive pathway. Choline can be oxidised to the methyl donor betaine, with short-term supplementation reported to lower plasma total homocysteine (tHcy); however, the effects of longer-term choline supplementation are less clear. We investigated the effect of choline supplementation on plasma concentrations of free choline, betaine and tHcy and B-vitamin status in postmenopausal women, a group more susceptible to low choline status. We also assessed whether supplementation altered plasma lipid profiles. In this randomised, double-blinded, placebo-controlled study, forty-two healthy postmenopausal women received 1 g choline per d (as choline bitartrate), or an identical placebo supplement with their habitual diet. Fasting blood samples were collected at baseline, week 6 and week 12. Administration of choline increased median choline and betaine concentrations in plasma, with significant effects evident after 6 weeks of supplementation (P<0·001) and remaining significant at 12 weeks (P<0·001); no effect was observed on folate status or on plasma lipids. Choline supplementation induced a median (25th, 75th percentile) change in plasma tHcy concentration at week 6 of -0·9 (-1·6, 0·2) μmol, a change which, when compared to that observed in the placebo group 0·6 (-0·4, 1·9) μmol, approached statistical significance (P=0·058). Choline supplementation at a dose of 1 g/d significantly increases the circulating concentration of free choline, and can also significantly increase the concentration of the methyl donor, betaine, thereby potentially enhancing the betaine-homocysteine methyltransferase-mediated remethylation of tHcy.

Diets high in palmitic acid (16:0), lauric and myristic acids (12:0 + 14:0), or oleic acid (18:1) do not alter postprandial or fasting plasma homocysteine and inflammatory markers in healthy Malaysian adults

Dietary fat type is known to modulate the plasma lipid profile, but its effects on plasma homocysteine and inflammatory markers are unclear. We investigated the effects of high-protein Malaysian diets prepared with palm olein, coconut oil (CO), or virgin olive oil on plasma homocysteine and selected markers of inflammation and cardiovascular disease (CVD) in healthy adults. A randomized-crossover intervention with 3 dietary sequences of 5 wk each was conducted in 45 healthy subjects. The 3 test fats, namely palmitic acid (16:0)-rich palm olein (PO), lauric and myristic acid (12:0 + 14:0)-rich CO, and oleic acid (18:1)-rich virgin olive oil (OO), were incorporated at two-thirds of 30% fat calories into high-protein Malaysian diets. No significant differences were observed in the effects of the 3 diets on plasma total homocysteine (tHcy) and the inflammatory markers TNF-α, IL-1β, IL-6, and IL-8, high-sensitivity C-reactive protein, and interferon-γ. Diets prepared with PO and OO had comparable nonhypercholesterolemic effects; the postprandial total cholesterol for both diets and all fasting lipid indexes for the OO diet were significantly lower (P < 0.05) than for the CO diet. Unlike the PO and OO diets, the CO diet was shown to decrease postprandial lipoprotein(a). Diets that were rich in saturated fatty acids prepared with either PO or CO, and an OO diet that was high in oleic acid, did not alter postprandial or fasting plasma concentrations of tHcy and selected inflammatory markers. This trial was registered at clinicaltrials.gov as NCT00941837.

Poor Folate Status Predicts Persistent Diarrhea in 6- to 30-Month-Old North Indian Children

Poor micronutrient status is associated with diarrheal illness, but it is not known whether low folate and/or cobalamin status are independent risk factors for diarrhea. We measured the association between plasma folate and cobalamin and subsequent diarrheal morbidity in a prospective cohort study of 2296 children aged 6–30 mo in New Delhi, India. Plasma concentrations of folate, cobalamin, total homocysteine (tHcy), and methylmalonic acid were determined at baseline. Whether a child had diarrhea was recorded during weekly visits in a 4-mo zinc supplementation trial. Diarrhea episodes lasting <7, ≥7, and ≥14 d were classified as acute, prolonged, and persistent, respectively. There was a total of 4596 child periods with acute, 633 with prolonged, and 117 with persistent diarrhea during follow-up. Children with plasma folate concentrations in the lowest quartile had higher odds of persistent diarrhea than children in the other quartiles [adjusted OR = 1.77 (95% CI = 1.14, 2.75); P = 0.01]. This effect differed between boys [adjusted OR = 2.51 (95% CI = 1.47, 4.28)] and girls [adjusted OR = 1.03 (95% CI = 0.53, 2.01); P-interaction = 0.030]. We found a small but significant association between high plasma tHcy concentration and acute diarrhea [adjusted OR = 1.14 (95% CI = 1.04, 1.24); P = 0.006]. Plasma cobalamin concentration was not a predictor of diarrheal morbidity. In conclusion, poor folate status was an independent predictor of persistent diarrhea in this population.

Modulator Effects of the Methylenetetrahydrofolate Reductase C677T Polymorphism on Response to Vitamin B12 Therapy and Homocysteine Metabolism

In this study, our aim was to investigate the association of methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism on the vitamin B12 therapy response in 95 patients with vitamin B12 deficiency and 92 healthy control subjects using vitamin B12, plasma total homocysteine (tHcy), and folate as the main measure of outcome. MTHFR C677T genotypes were determined by polymerase chain reaction-restriction fragment length polymorphism techniques. There were no differences in the distribution of MTHFR genotypes in the cases versus the controls. Mean concentrations of plasma tHcy and B12 vitamin were 18.84 μM and 142.47 pg/mL in patients with TT (10.5%) genotypes. Furthermore, mean concentrations of B12 vitamin after cobalamin therapy were 697.62, 656.64, and 488.76 pg/mL in patients with the CC, CT, and TT genotypes, respectively. The MTHFR 677 TT genotype has decreasing effect in B12 vitamin and increasing effect in tHcy. In comparison with the patients having CC and CT genotypes, patients with the TT genotype had a lower response to vitamin B12 therapy.

Child's homocysteine concentration at 2 years is influenced by pregnancy vitamin B12 and folate status.

Longitudinal studies investigating vitamin B12 and folate status of mothers and their offspring will provide a better understanding of intergenerational nutrition. During pregnancy and 2 years (2y) after delivery, we measured plasma vitamin B12 and folate concentrations in 118 women [aged (mean ± s.d.) 22.9 ± 3.9y] who attended a rural (n = 68) or an urban (n = 50) antenatal clinic in Pune, India. Cord blood vitamin B12 and folate were measured, and when the child was 2y total homocysteine (tHcy) was also measured. Demographic and diet measurements were recorded using standard methods. Pregnancy plasma vitamin B12 concentration at 34 weeks was low [median (25th, 75th), 115 (95, 147) pm]; 75% had low status (<150 pm). Plasma folate was high (mean ± s.d., 33 ± 21 nm); one had a folate concentration <7 pm. Cord plasma vitamin B12 and folate concentrations were higher than and positively associated with maternal concentrations. In stepwise regression, higher child vitamin B12 at 2y was predicted (total R 2 15.7%) by pregnancy vitamin B12 (std β 0.201, R 2 7.7%), current consumption of cow's milk (std β 0.194, R 2 3.3%) and whether breast feeding was stopped before 2y (std β -0.234 R 2 7.2%). Child's 2y tHcy concentration was high (11.4 ± 3.6 μm) and predicted by lower pregnancy vitamin B12 (std β -0.206, R 2 4.1%), lack of vitamin supplementation (std β -0.256, R 2 5.6%) in pregnancy and whether currently breastfed (std β 0.268, R 2 8.4%). Low maternal vitamin B12 status in pregnancy and prolonged breast-feeding results in disturbed one-carbon metabolism in offspring at 2y. Supplementation of women of child-bearing age, particularly during pregnancy and lactation, may improve the homocysteine status of these children.

Deletion of Betaine-Homocysteine S-Methyltransferase in Mice Perturbs Choline and 1-Carbon Metabolism, Resulting in Fatty Liver and Hepatocellular Carcinomas

Betaine-homocysteine S-methyltransferase (BHMT) uses betaine to catalyze the conversion of homocysteine (Hcy) to methionine. There are common genetic polymorphisms in the BHMT gene in humans that can alter its enzymatic activity. We generated the first Bhmt(-/-) mouse to model the functional effects of mutations that result in reduced BHMT activity. Deletion of Bhmt resulted in a 6-fold increase (p < 0.01) in hepatic and an 8-fold increase (p < 0.01) in plasma total Hcy concentrations. Deletion of Bhmt resulted in a 43% reduction in hepatic S-adenosylmethionine (AdoMet) (p < 0.01) and a 3-fold increase in hepatic S-adenosylhomocysteine (AdoHcy) (p < 0.01) concentrations, resulting in a 75% reduction in methylation potential (AdoMet:AdoHcy) (p < 0.01). Bhmt(-/-) mice accumulated betaine in most tissues, including a 21-fold increase in the liver concentration compared with wild type (WT) (p < 0.01). These mice had lower concentrations of choline, phosphocholine, glycerophosphocholine, phosphatidylcholine, and sphingomyelin in several tissues. At 5 weeks of age, Bhmt(-/-) mice had 36% lower total hepatic phospholipid concentrations and a 6-fold increase in hepatic triacyglycerol concentrations compared with WT (p < 0.01), which was due to a decrease in the secretion of very low density lipoproteins. At 1 year of age, 64% of Bhmt(-/-) mice had visible hepatic tumors. Histopathological analysis revealed that Bhmt(-/-) mice developed hepatocellular carcinoma or carcinoma precursors. These results indicate that BHMT has an important role in Hcy, choline, and one-carbon homeostasis. A lack of Bhmt also affects susceptibility to fatty liver and hepatocellular carcinoma. We suggest that functional polymorphisms in BHMT that significantly reduce activity may have similar effects in humans.

Serum homocysteine and folate but not vitamin B12 are predictors of CHD mortality in older adults

The associations of serum levels of homocysteine (tHcy), vitamin B(12), and folate with risk of all-cause and coronary heat disease (CHD) mortality is controversial, and the evidence in older adults is limited. The aim of this study was to examine whether serum folate, vitamin B(12), and tHcy independently predict risk of CHD-related and all-cause mortality in older adults. Serum concentrations of folate, vitamin B(12), and tHcy were determined from blood samples obtained from 3010 Blue Mountains Eye Study participants (1997-99), aged ≥55 years. CHD and all-cause mortality was confirmed using the Australian National Death Index. Persons in the highest quartile of serum tHcy had increased risk of CHD mortality compared to those in the lowest quartile (multivariable-adjusted hazard ratio, HR, 2.45, 95% CI 1.30-4.62). A significant continuous association was observed between serum tHcy and CHD mortality (HR per SD ( = 4.8 µmol/l) increase in serum tHcy 1.25, 95% CI 1.08-1.45), after multivariable-adjustment. A significant association between folate deficiency and CHD-mortality was found (multivariable-adjusted HR 1.53, 95% CI 1.01-2.29). Hyperhomocysteinaemia (>15 µmol/l) was a significant predictor of all-cause mortality (multivariable-adjusted HR 1.47, 95% CI 1.18-1.83). A significant interaction was observed between hyperhomocysteinaemia and folate deficiency for all-cause and CHD mortality (p for interaction = 0.03 and p for interaction = 0.05, respectively). Serum tHcy and folate were independent predictors of CHD and all-cause mortality, while vitamin B(12) was not associated. As raised tHcy levels and folate deficiency are associated with poorer lifestyle, changes to a more healthful lifestyle among older adults may minimize the adverse vascular effects of elevated tHcy.

THE RELATIONSHIP BETWEEN DDT UPTAKE, HORMONAL CHANGES AND CIRCULATING HOMOCYSTEINE CONCENTRATIONS

Background and aims: As sex hormones reportedly alter homocysteine metabolism, we hypothesised that pesticides that exert anti-androgenic and estrogenic may affect total homocysteine (t-Hcy) concentrations. Plasma samples for total homocysteine (t-Hcy) were collected during some of the visits of an on-going cross-sectional study evaluating male fertility parameters with Indoor Residual Spraying (IRS). Methods: The t-Hcy concentration and its determinants, estradiol (E2) and testosterone sub-fractions, and SHBG and Albumin were compared between young males from sprayed (n=219) and unsprayed villages (n=215), taking the variance of the data and co-variates into account. Regression analyses were performed in the exposure group. Results: The mean (SD) t-Hcy concentrations in sprayed villages were significantly lower (7.7(2.4) vs 8.3(2.5) µmol/L; p&lt;0.05), while t-Hcy determinant concentrations did not differ significantly. Lowertotal testosterone (t-T) concentrations (21.3(6.0) vs 25.2(9.1) nmol/L; p&lt;0.001), % bio-available testosterone (%bio-T) (40.9(8.3) vs 50.3(14.5); p&lt;0.005), albumin (44.8(4.5) vs 46.0(6.0) mg/dL; p&lt;0.05) and E2 concentrations (115.6(32.5) vs 136.2(36.8) pmol/L; p&lt;0.001) were observed in non-sprayed villages. After correcting for vitamin B12 and either p,p’DDE or p,p’DDT, t-Hcy concentration no longer differed significantly between groups. In sprayed villages significant Spearman rank correlation coefficients were observed for t-Hcy with p,p’DDE, p,p’DDT,and bio-T (respective r-values: -0.260, -0.289, 0.197; p&lt;0.005). When comparing regression lines for Log_Hcy = %bio_T, the slopes did not differ significantly between groups, while elevation differed significantly (F=7.28, DF=1, 423, p= 0.007). Concentration-dependent linear trends were observed, using Polynomial contrast, across p,p’DDE and p,p’DDT quartiles for Log-Hcy (decreasing) and for serum creatinine (increasing) (p&lt;0.001). Conclusions: Lower t-Hcy concentrations appear to be related to DDT uptake. This stucy does not explain these findings. Association between t-Hcy and sex hormones is not clearly evident, except for the association with %bio-T. What is apparent is that uptake of DDT may be associated with altered sex hormone and homocysteine homeostasis.

Marked Gender Difference in Plasma Total Homocysteine Concentrations in Indian Adults with low Vitamin B12

Plasma total homocysteine (tHcy) is higher in men than women. To explore the gender differences in tHcy in relation to determinants of one-carbon metabolism in Indian people with low B₁₂ and adequate folate. The study took place in rural and urban areas of Pune, India. Participants were 441 men from the cross-sectional Coronary Risk of Insulin Sensitivity in Indian Subjects study (CRISIS) and premenopausal wives of 146 men (median ages 38 and 34 years, respectively). Gender difference in fasting tHcy in relation to plasma albumin and creatinine concentrations, lifestyle factors, diet and lean mass, plasma B₁₂ and red cell folate (RCF) was assessed. Prevalence of high tHcy (> 15 µmol/L, median 14.4 µM) was 40 %, low B12 (< 150 pmol/L, 114 pmol/L) 66 %, and low RCF (< 283 nmol/L, 525 nmol/L) 8 %. Men had higher (1.8x) plasma tHcy concentrations (16.2 µmol/L) than women (9.5 µmol/L). Only 50 % of the gender difference was explained by age, lean mass, B₁₂, and RCF. The difference remained after controlling for other explanatory variables. Women with a tHcy of 9.3 µM had the same B₁₂ concentration (129 pmol/L) as men with a tHcy of 15 µM; and for a tHcy of 10.0 µmol/L women had the same RCF concentration (533 nmol/L) as men with a tHcy of 15 µmol/L. Adult Indian women have markedly lower tHcy concentrations compared to men. This suggests a lower threshold for supplementation to improve reproductive and cardiovascular outcomes.

Folate and vitamin B12 in idiopathic male infertility

Although methylenetetrahydrofolate reductase, a folate enzyme gene, has been associated with idiopathic male infertility, few studies have examined other folate-related metabolites and genes. We investigated whether idiopathic male infertility is associated with variants in folate, vitamin B(12) (B12) and total homocysteine (tHcy)-related genes and measured these metabolites in blood. We conducted a case-control study that included 153 men with idiopathic infertility and 184 fertile male controls recruited at the Fertility Center and Antenatal Care Center, University Hospital, Malmö and Lund, Sweden. Serum folate, red cell folate (RCF), serum B12, plasma tHcy and semen quality were measured. Subjects were genotyped for 20 common variants in 12 genes related to folate/B12/homocysteine metabolism. Metabolite concentrations and genotype distributions were compared between cases and controls using linear and logistic regression with adjustment for covariates. The phosphatidylethanolamine N-methyltransferase (PEMT) M175V and TCblR rs173665 polymorphisms were significantly associated with infertility (P=0.01 and P=0.009, respectively), but not with semen quality. Among non-users of supplements, infertile men had lower serum folate concentrations than fertile men (12.89 vs. 14.73 nmol l(-1); P=0.02), but there were no significant differences in RCF, B12 or tHcy. Folate, B12 and tHcy concentrations were not correlated with any semen parameters. This study provides little support for low folate or B12 status in the pathogenesis of idiopathic male infertility. Although additional data are needed to confirm these initial findings, our results suggest that PEMT and TCblR, genes involved in choline and B12 metabolism, merit further investigation in idiopathic male infertility.

Dietary Micronutrient Intakes Are Associated with Markers of Inflammation but Not with Markers of Subclinical Atherosclerosis ,

Few studies have examined associations of dietary micronutrients with markers of inflammation and subclinical atherosclerosis. The present study investigated associations of heme iron, nonheme iron, zinc (Zn), magnesium (Mg), β-carotene, vitamin C, and vitamin E with C-reactive protein (CRP), IL-6, total homocysteine (tHcy), fibrinogen, coronary artery calcium, and common and internal carotid artery intima media thickness. Micronutrient intakes and markers of inflammation and subclinical atherosclerosis were studied in 5,181 participants from the Multi-Ethnic Study of Atherosclerosis who were aged 45-84 y and free of diabetes and cardiovascular disease. Models were adjusted for energy intake, demographics, lifestyle characteristics, and BMI. Dietary nonheme iron and Mg intakes were inversely associated with tHcy concentrations (mean tHcy: 9.11, 8.86, 8.74, 8.71, and 8.50 μmol/L, and 9.20, 9.00, 8.65, 8.76, and 8.33 μmol/L across increasing quintiles of nonheme iron and Mg, respectively; P-trend < 0.001 for both). However, dietary Zn and heme iron were positively associated with CRP [mean: 1.73, 1.75, 1.78, 1.88, and 1.96 mg/L across increasing quintiles of Zn and 1.72, 1.76, 1.83, 1.86, and 1.94 mg/L across increasing quintiles of heme iron (P-trend = 0.002 and 0.01, respectively). Other tested micronutrient-marker associations were not significant. In conclusion, of the 49 tested associations, only 7 were significant. Although this study does not provide strong support for associations between the micronutrients and markers of inflammation and subclinical atherosclerosis, the results are consistent with dietary guidelines that advocate for a balanced diet that includes a variety of plant foods containing Mg, Zn, and nonheme iron.