Higher Folate Concentrations Research Articles

High homocysteine and low folate plasma concentrations are associated with cardiovascular events but not bleeding during warfarin treatment.

Previous studies have shown that homocysteine and folate levels in plasma are associated with risk for cardiovascular events and mortality. The aim of this study was to investigate if plasma concentrations of total homocysteine and folate can predict major bleeding, cardiovascular events, and all-cause mortality in patients being treated with warfarin. In a longitudinal cohort study, 719 patients who were taking warfarin were followed for 3001 treatment years. The following were recorded and classified: major bleeding; cardiovascular events including stroke, arterial emboli, and myocardial infarction (MI); and mortality. Blood samples collected at baseline were analysed for plasma homocysteine and folate levels. After adjustment for age, C-reactive protein, and creatinine, high homocysteine levels were associated with cardiovascular events [hazard ratio (HR) 1.23 per standard deviation (SD); 95% confidence interval (CI): 1.03-1.47], MI (HR 1.38 per SD; 95% CI: 1.03-1.85), and all-cause mortality (HR 1.41 per SD; 95% CI: 1.19-1.68). The highest tertile of folate compared to the lowest tertile was associated with decreased risk for both cardiovascular events (HR 0.64; 95% CI: 0.43-0.91) and MI (HR 0.45; 95% CI: 0.21-0.97). There was no association between major bleeding and homocysteine or folate levels. In patients receiving warfarin treatment, high homocysteine and low folate plasma concentrations are associated with increased risk for cardiovascular events but not major bleeding. For homocysteine levels, there is also an association with all-cause mortality.

Maternal and Neonatal Markers of the Homocysteine Pathway and Fetal Growth: The Generation R Study.

Suboptimal dietary intake during pregnancy may have long-term health implications in children. These effects may be mediated by fetal growth. We investigated the associations of early pregnancy and umbilical cord total homocysteine (tHcy), folate, and total and active vitamin B12 concentrations with fetal growth parameters repeatedly measured in pregnancy and at birth. This study was performed in 5890 pregnant women, participating in a population-based prospective cohort study. Blood samples were obtained from women in early pregnancy and from the umbilical vein at delivery. Fetal size parameters were repeatedly measured by ultrasound. Information about birth anthropometrics was retrieved from medical records. High early pregnancy maternal tHcy (≥8.31μmol/L), as compared with low maternal homocysteine (≤5.80μmol/L), and low early pregnancy maternal folate (≤9.10nmol/L), as compared with high maternal folate (≥25.81nmol/L) concentrations, were associated with reduced weight growth patterns throughout pregnancy, resulting in birthweight differences of -102.3 g (95% CI -139.6, -65.0) and -113.0g (95% CI -159.6, -66.3), respectively. Low umbilical cord folate concentrations (≤15.20nmol/L) as compared with high umbilical cord folate concentrations (≥28.41nmol/L) were also associated with a lower birthweight and birth length (P<0.001). Interestingly, compared with higher umbilical cord vitamin B12 , lower vitamin B12 concentrations were associated with a higher weight, length, and head circumference at birth (P<0.01). Early pregnancy maternal and umbilical cord markers of the homocysteine pathway are significantly associated with fetal growth patterns. These differences arise from mid-pregnancy onwards.

Circulating Folate and Vitamin B12 and Risk of Prostate Cancer: A Collaborative Analysis of Individual Participant Data from Six Cohorts Including 6875 Cases and 8104 Controls

BackgroundFolate and vitamin B12 are essential for maintaining DNA integrity and may influence prostate cancer (PCa) risk, but the association with clinically relevant, advanced stage, and high-grade disease is unclear. ObjectiveTo investigate the associations between circulating folate and vitamin B12 concentrations and risk of PCa overall and by disease stage and grade. Design, setting, and participantsA study was performed with a nested case–control design based on individual participant data from six cohort studies including 6875 cases and 8104 controls; blood collection from 1981 to 2008, and an average follow-up of 8.9 yr (standard deviation 7.3). Odds ratios (ORs) of incident PCa by study-specific fifths of circulating folate and vitamin B12 were calculated using multivariable adjusted conditional logistic regression. Outcome measurements and statistical analysisIncident PCa and subtype by stage and grade. Results and limitationsHigher folate and vitamin B12 concentrations were associated with a small increase in risk of PCa (ORs for the top vs bottom fifths were 1.13 [95% confidence interval (CI), 1.02–1.26], ptrend=0.018, for folate and 1.12 [95% CI, 1.01–1.25], ptrend=0.017, for vitamin B12), with no evidence of heterogeneity between studies. The association with folate varied by tumour grade (pheterogeneity<0.001); higher folate concentration was associated with an elevated risk of high-grade disease (OR for the top vs bottom fifth: 2.30 [95% CI, 1.28–4.12]; ptrend=0.001), with no association for low-grade disease. There was no evidence of heterogeneity in the association of folate with risk by stage or of vitamin B12 with risk by stage or grade of disease (pheterogeneity>0.05). Use of single blood-sample measurements of folate and B12 concentrations is a limitation. ConclusionsThe association between higher folate concentration and risk of high-grade disease, not evident for low-grade disease, suggests a possible role for folate in the progression of clinically relevant PCa and warrants further investigation. Patient summaryFolate, a vitamin obtained from foods and supplements, is important for maintaining cell health. In this study, however, men with higher blood folate levels were at greater risk of high-grade (more aggressive) prostate cancer compared with men with lower folate levels. Further research is needed to investigate the possible role of folate in the progression of this disease.

Serum folate levels and fatality among diabetic adults: A 15-y follow-up study of a national cohort

ObjectiveFolate is involved in carbohydrate metabolism, a process that can have clinical implications regarding diabetes management. The aim of this study was to assess the relationship between serum folate and fatality among adults with diabetes. MethodsA retrospective cohort study was conducted with 532 adults with diabetes who participated in Phase II of NHANES III (National Health and Nutrition Examination Survey III; 1991–1994). This study served as baseline and was linked to the National Death Index database for a 15-y (1991–2006) follow-up study. Estimates of hazard ratios (HRs) for all-cause and cancer-related deaths, cardiovascular disease (CVD), and diabetes for individuals with different serum folate levels were obtained from Cox proportional hazards regression. ResultsThe mean age of adults with diabetes and detected serum folate at baseline was 63.2 y (SD 13.8 y). During follow-up, diabetes was listed as a contributor for 138 of 299 deaths. For all-cause deaths, the fatality rate of the upper quartile (74.30/1000 person-years [PY]) was almost twofold higher than the lower quartile (41.75/1000 PY) of serum folate levels. After adjusting for several covariates, including serum vitamin B12, cotinine, homocysteine and CVD history at baseline; the HRs for all-cause fatalities were 1.00 (reference), 1.62 (95% confidence interval [CI], 1.06–2.47) and 1.76 (95% CI, 1.09–2.83) among adults with diabetes in the lower, intermediate, and upper quartiles of serum folate levels, respectively. ConclusionResults indicate that high serum folate concentrations are associated with an increased fatality risk among adults with diabetes. Further studies are warranted to determine the mechanism(s) of this phenomenon.

High concentrations of folate and unmetabolized folic acid in a cohort of pregnant Canadian women and umbilical cord blood

Mandatory fortification, prevalent supplement use, and public health guidelines recommending periconceptional supplementation have increased folic acid intakes in North American pregnant women. However, the effects of increased folic acid intakes during pregnancy on maternal and cord blood folate concentrations have not been well established. In this prospective study, we determined maternal and cord blood concentrations of folate and unmetabolized folic acid (UMFA) in a cohort of pregnant Canadian women and their newborns and examined the effect of maternal intakes of folate and folic acid and fetal genetic variants in folate metabolism on folate status. Folate and folic acid intakes of 368 Canadian pregnant women were assessed in early (0-16 wk) and late (23-37 wk) pregnancy. Blood concentrations of folate and UMFA were measured with the use of immunoassays and liquid chromatography-mass spectrometry, respectively, in maternal samples in early pregnancy (12-16 wk), at delivery (28-42 wk), and in cord blood. Four fetal genetic variants of the 5,10-methylenetetrahydrofolate reductase (MTHFR) and dihydrofolate reductase (DHFR) genes were assessed for their association with cord blood concentrations of folate and UMFA. Geometric mean (95% CI) maternal red blood cell (RBC) folate concentrations were 2417 nmol/L (2362, 2472 nmol/L ) and 2793 nmol/L (2721, 2867 nmol/L ) in early pregnancy and at delivery, respectively. The mean (95% CI) cord RBC folate concentration was 2689 nmol/L (2614, 2765 nmol/L). UMFA was detectable in >90% of maternal and cord plasma samples. Although 3 fetal MTHFR and DHFR genetic variants had no effect, the fetal MTHFR 677TT genotype was associated with significantly lower cord serum (P = 0.03) and higher cord RBC (P = 0.02) folate concentrations than those of the wild type. Notwithstanding differences in assays, maternal and cord RBC folate and plasma UMFA concentrations were higher than previously reported values. Functional ramifications of high folate and UMFA concentrations in maternal and fetal circulation warrant additional investigation because an excess folate status may affect long-term health outcomes of the offspring. This study was registered at www.clinicaltrials.gov as NCT02244684.

High red blood cell folate is associated with an increased risk of death among adults with diabetes, a 15-year follow-up of a national cohort

Background and aimTo describe the mortality and fatality of diabetes and assess their relationship with the level of red blood cell (RBC) folate. Methods and resultWe analyzed the data of 526 adults with diabetes who participated in the National Health and Nutrition Examination Survey (1991–1994) as the baseline examination, and were followed up through December 31, 2006. Estimates of the hazard ratios (HRs) of selected death causes for individuals with different levels of RBC folate were obtained from Cox proportional hazards regression. A total of 295 deaths were recorded by the end of a 15-year follow-up with a mortality rate of 58.48 per 1000 person year (py). Diabetes was listed as a contributing cause for 136 deaths, accounting for 46.1% of the total deaths with a fatality rate 26.96 per 1000 py. Mortality rate for all-cause in the group with upper quartile of RBC folate was almost twice as high as that among the group with lower quartile, 82.75 vs. 44.10 per 1000 py. After adjusting for covariates, including serum concentration of vitamin B12, cotinine, homocysteine and the history of cardio-cerebral vascular diseases assessed at the baseline, the HRs for dying from any causes were 1.00 (reference), 1.82 (95% CI = 1.25–2.66) and 2.10 (1.37–3.20) among diabetic adults with lower, intermediate, and upper quartiles of RBC folate. ConclusionDiabetes was listed as a contributing cause for less than half of the deaths among adults with diabetes after 15+ years of follow-up; high RBC folate concentration was associated with an elevated risk of death among adults with diabetes.

Systematic review of adverse health outcomes associated with high serum or red blood cell folate concentrations.

To examine the relationship between reported high serum or red blood cell (RBC) folate status and adverse health outcomes. We systematically searched PubMed/Medline and EMBASE (to May 2013), with no limits by study type, country or population, to identify studies reporting high folate concentrations in association with adverse health outcomes. Two reviewers screened studies and extracted data. Study quality was assessed. We included 51 articles, representing 46 studies and 71 847 participants. Quantiles were used by 96% of studies to identify high folate concentrations. Eighty-three percent of serum folate and 50% of RBC folate studies reported a high folate cutoff that corresponded with a clinically normal concentration. Increasing values of reported high folate concentration did not demonstrate a consistent association with risk of adverse health outcomes. Overall, reported high folate concentrations appeared to be associated with a decreased risk of adverse health outcomes, though substantial methodological heterogeneity precluded complex analyses. Our interpretation was complicated by methodological variability. High folate cutoffs varied and often corresponded with normal or desirable blood concentrations. In general, a negative association appeared to exist between reported high folate status and adverse health outcomes. Consistent methods and definitions are needed to examine high folate status and ultimately inform public health interventions.

Prevalence and correlates of high red blood cell folate concentrations in the Canadian population using 3 proposed cut-offs.

A distinct shift towards higher folate concentrations has emerged in Canada. These higher concentrations have known benefits, including prevention of neural tube defects, but concerns have been raised regarding potential associations with adverse health outcomes. The aim of this research was to propose cut-offs for high red blood cell (RBC) folate concentrations and identify their correlates. RBC folate was measured in a nationally representative cross-sectional sample of Canadians (N = 5248) aged 6 to 79 years. RBC folate concentrations were adjusted from the IMMULITE 2000 immunoassay to a microbiologic assay. The population was characterized at 3 RBC folate cut-offs: 1450 nmol/L, 1800 nmol/L, and 2150 nmol/L. We used t tests to examine differences by age, sex, income, and body mass index (BMI) at each cut-off and logistic regression to explore associations with folic acid supplement intake. The prevalence of high RBC folate was 16%, 6%, and 2% at thresholds of 1450 nmol/L, 1800 nmol/L, and 2150 nmol/L, respectively. Females, those aged 60 to 79 years, and overweight or obese participants had the greatest prevalence of having high RBC folate at each cut-off. Folic acid supplement users were more likely than non-users to have high RBC folate concentrations. Older age, higher BMI, and folic acid supplement use were identified as correlates of high folate status. A high RBC folate concentration cut-off will advance the field towards consistent measurement and reporting of high folate status. This may facilitate future investigation of associations between RBC folate concentrations at the upper end of the distribution and health outcomes.

Vitamin paradox in obesity: Deficiency or excess?

Since synthetic vitamins were used to fortify food and as supplements in the late 1930s, vitamin intake has significantly increased. This has been accompanied by an increased prevalence of obesity, a condition associated with diabetes, hypertension, cardiovascular disease, asthma and cancer. Paradoxically, obesity is often associated with low levels of fasting serum vitamins, such as folate and vitamin D. Recent studies on folic acid fortification have revealed another paradoxical phenomenon: obesity exhibits low fasting serum but high erythrocyte folate concentrations, with high levels of serum folate oxidation products. High erythrocyte folate status is known to reflect long-term excess folic acid intake, while increased folate oxidation products suggest an increased folate degradation because obesity shows an increased activity of cytochrome P450 2E1, a monooxygenase enzyme that can use folic acid as a substrate. There is also evidence that obesity increases niacin degradation, manifested by increased activity/expression of niacin-degrading enzymes and high levels of niacin metabolites. Moreover, obesity most commonly occurs in those with a low excretory reserve capacity (e.g., due to low birth weight/preterm birth) and/or a low sweat gland activity (black race and physical inactivity). These lines of evidence raise the possibility that low fasting serum vitamin status in obesity may be a compensatory response to chronic excess vitamin intake, rather than vitamin deficiency, and that obesity could be one of the manifestations of chronic vitamin poisoning. In this article, we discuss vitamin paradox in obesity from the perspective of vitamin homeostasis.

Applicability of a Lactobacillus amylovorus strain as co-culture for natural folate bio-enrichment of fermented milk

The ability of 55 strains from different Lactobacillus species to produce folate was investigated. In order to evaluate folic acid productivity, lactobacilli were cultivated in the folate-free culture medium (FACM). Most of the tested strains needed folate for growth. The production and the extent of vitamin accumulation were distinctive features of individual strains. Lactobacillus amylovorus CRL887 was selected for further studies because of its ability to produce significantly higher concentrations of vitamin (81.2±5.4μg/L). The safety of this newly identified folate producing strain was evaluated through healthy experimental mice. No bacterial translocation was detected in liver and spleen after consumption of CRL887 during 7 days and no undesirable side effects were observed in the animals that received this strain. This strain in co-culture with previously selected folate producing starter cultures (Lactobacillus bulgaricus CRL871, and Streptococcus thermophilus CRL803 and CRL415) yielded a yogurt containing high folate concentrations (263.1±2.4μg/L); a single portion of which would provide 15% of the recommended dietary allowance. This is the first report where a Lactobacillus amylovorus strain was successfully used as co-culture for natural folate bio-enrichment of fermented milk.

Examining the folate status of Canadians: An analysis of the Canadian Health Measures Survey to assess and guide folate policies

Canada fortifies certain products with folic acid and has periconceptional supplementation guidelines [Formula: see text] policies designed to improve folate status and reduce the incidence of poor birth outcomes. Though optimal folate concentrations have been linked to health benefits, concerns have been raised regarding potential associations with adverse health outcomes. Direct biochemical assessment of the folate status of Canadians based on a nationally representative sample has not been done in more than 40 years. The overall purpose of this research was to investigate the folate status of the Canadian population. All analyses used the nationally representative 2007–2009 Canadian Health Measures Survey (CHMS). Red blood cell (RBC) folate was measured by Immulite 2000 immunoassay. Key findings indicate that folate deficiency (&lt;305 nmol/L) was virtually nonexistent in the Canadian population (6–79 years old). Still, one-fifth of women of childbearing age (WCBA; 15–45 years old) had suboptimal concentrations for the prevention of neural tube defects (&lt;906 nmol/L). Folic acid supplement intake was a primary determinant of WCBA, achieving a RBC folate concentration of ≥906 nmol/L. A distinct shift towards elevated RBC folate concentrations emerged. Three hypothetical cut-offs (1450 nmol/L, 1800 nmol/L and 2150 nmol/L) were examined to create a dialogue since a universal definition of high RBC folate concentration does not exist. Females, participants aged 60–79 years, and those who were overweight or obese had the greatest prevalence of having high RBC folate at each cut-off. We conducted the first national-level comparison of RBC folate concentrations between the United States and Canada. Two different folate assay methods [Formula: see text] microbiologic assay (NHANES) and Immulite 2000 immunoassay (CHMS) [Formula: see text] necessitated the application of a conversion equation. Median Canadian RBC folate concentrations (adjusted to microbiologic assay) were lower than those of Americans but unadjusted Canadian median RBC folate values were higher. Canadian WCBA were less likely than American WCBA to have RBC folate ≥906 nmol/L, though Canadian WCBA with unadjusted RBC folate values were more likely to achieve this cut-off. These results indicate a need for strategies targeting WCBA to improve compliance with folic acid supplement recommendations. The strength and necessity of supplements for the general population should be re-assessed. Further, harmonization of folate measurement procedures in future surveillance efforts would support comparisons and inform policy directions.

Extremely high concentration of folates in premature newborns

Extremely high concentration of folates in premature newborns: case reports. Folates are a group of water soluble compounds, which are important for metabolic processes in human body. These are important during periods of rapid cell growth. The most accurate indicator of long-term folate level status in the body is the determination of red blood cell (RBC) folate concentrations. The optimal level of RBC folate is not known in neonatal period. Authors discuss the reasons for extremely high level of RBC folate concentrations. In our work we present the cases of two premature newborns with extremely high level of RBC folate concentrations, which were analyzed immunochemically on the first day of life and after six weeks of life. In both cases we measured RBC folate concentrations on the 1st day of life. After 6 weeks we found extremely high RBC folate concentration level (5516.67 ng/ml) in the first case after RBC transfusions. In second case after two months of life the RBC folate concentration level was doubled (2335.1 ng/ml) until 24 hours after RBC transfusion compared to levels after birth. The normal range of RBC folate values vary in newborns. The upper limit of daily dose of folic acid in pregnancy and neonatal period is not known. On the other hand it is an easily excreted water-soluble vitamin but in premature newborn it can lead to the disruption of metabolic balance and slow its degradation. Some factors can have an impact on RBC folate concentration. Blood transfusion can be one of the main influences on RBC folate concentration. To clarify these mechanisms further studies are required (Ref. 29).

Association between maternal folate concentrations during pregnancy and insulin resistance in Indian children

Aims/hypothesisIn an Indian birth cohort, higher maternal homocysteine concentration in pregnancy was associated with lower birthweight of the offspring. Lower maternal vitamin B12 and higher folate concentrations were associated with higher offspring insulin resistance. Disordered one-carbon metabolism during early development may increase later metabolic risk. We explored these associations in another birth cohort in India at three age points.MethodsWe measured plasma vitamin B12, folate and homocysteine concentrations at 30 ± 2 weeks’ gestation in 654 women who delivered at one hospital. Neonatal anthropometry was recorded, and the children’s glucose and insulin concentrations were measured at 5, 9.5 and 13.5 years of age. Insulin resistance was estimated using HOMA of insulin resistance (HOMA-IR).ResultsMaternal homocysteine concentrations were inversely associated with all neonatal anthropometric measurements (p < 0.05), and positively associated with glucose concentrations in the children at 5 (30 min; p = 0.007) and 9.5 years of age (120 min; p = 0.02). Higher maternal folate concentrations were associated with higher HOMA-IR in the children at 9.5 (p = 0.03) and 13.5 years of age (p = 0.03). Maternal vitamin B12 concentrations were unrelated to offspring outcomes.Conclusions/interpretationMaternal vitamin B12 status did not predict insulin resistance in our cohort. However, associations of maternal homocysteine and folate concentrations with birth size, and with childhood insulin resistance and glycaemia in the offspring, suggest a role for nutritionally driven disturbances in one-carbon metabolism in fetal programming of diabetes.Electronic supplementary materialThe online version of this article (doi:10.1007/s00125-013-3086-7) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

γ-Glutamyl hydrolase modulation and folate influence chemosensitivity of cancer cells to 5-fluorouracil and methotrexate

Background:γ-Glutamyl hydrolase (GGH) regulates intracellular folate and antifolates for optimal nucleotide biosynthesis and antifolate-induced cytotoxicity, respectively. The modulation of GGH may therefore affect chemosensitivity of cancer cells, and exogenous folate levels may further modify this effect.Methods:We generated a novel model of GGH modulation in human HCT116 and MDA-MB-435 cancer cells and investigated the effect of GGH modulation on chemosensitivity to 5-fluorouracil (5FU) and methotrexate (MTX) at different folate concentrations in vitro and in vivo.Results:Overexpression of GGH significantly decreased chemosensitivity of MDA-MB-435 cells to 5FU and MTX at all folate concentrations as expected. In contrast, in HCT116 cells this predicted effect was observed only at very high folate concentration, and as the folate concentration decreased this effect became null or paradoxically increased. This in vitro observation was confirmed in vivo. Inhibition of GGH significantly increased chemosensitivity of both cancer cells to 5FU at all folate concentrations. Unexpectedly, GGH inhibition significantly decreased chemosensitivity of both cancer cells to MTX at all folate concentrations. In both GGH modulation systems and cell lines, the magnitude of chemosensitivity effect incrementally increased as folate concentration increased.Conclusion:Modulation of GGH affects chemosensitivity of cancer cells to 5FU and MTX, and exogenous folate levels can further modify the effects.

Development of a high folate concentration yogurt naturally bio-enriched using selected lactic acid bacteria

Folate concentrations in yogurts vary widely and are normally considered low due to an inadequate selection of starter cultures and fermentation conditions. In this study, folate producing Lactobacillus delbrueckii subsp. bulgaricus (3 strains) and Streptococcus thermophilus (2 strains) were combined and used to elaborate 15 different yogurts. Samples were taken at different time points during the fermentation process and folate concentrations were determined. The yogurt elaborated with strains CRL871 + CRL803 + CRL415 and incubated at 42 °C had significantly higher folate concentrations (reaching 180 ± 10 μg/L) which implies almost a 250% increase in respect to non-fermented milk, and about 125% compared to commercial yogurts. No variations in folate concentration were observed during 28 days of storage at 4 °C. This is the first report of a yogurt naturally bio-enriched in folate using native folate producing starter cultures.

Serum Folate but Not Vitamin B-12 Concentrations Are Positively Associated with Cognitive Test Scores in Children Aged 6–16 Years

Folate and vitamin B-12 are important for nervous system functioning at all ages, with important roles in functions such as neurotransmitter synthesis. Although studies suggest a relation between folate and vitamin B-12 and cognitive function in the elderly population, there is relatively less evidence regarding these vitamins and children's cognitive function. The purpose of the study was to examine the associations of serum folate and vitamin B-12 with cognitive performance in children 6–16 y old in the NHANES III, conducted from 1988 to 1994, prior to the implementation of folic acid fortification. A cross-sectional analysis was conducted using data on 5365 children 6–16 y old from NHANES III. Serum folate and vitamin B-12 concentrations were measured, along with performance, on the Wide Range Achievement Test-Revised and the Wechsler Intelligence Scale for Children-Revised. Associations of B vitamins with cognitive performance were assessed using linear regression models adjusted for various covariates. Higher serum concentrations of folate were associated with higher reading and block design scores after adjusting for various covariates. For example, compared with the lowest quartile of folate, children in the highest quartile scored 3.28 points or 0.19 SD units higher on the reading test (P < 0.05). Vitamin B-12 was not associated with any of the test scores. In the largest study to date, higher folate concentrations were associated with better reading and block design scores. These associations appear to be biologically plausible and merit further study.

Folic acid supplementation for 12 weeks modifies gene expression in leukocytes in men with low folate status

Folate nutritional status and the 677C&gt;;T polymorphism of methylene tetrahydrofolate reductase (MTHFR) are known to influence gene expression. The objective of this study was to determine if supplementation with 400μg of folic acid for a period of 12 weeks will change gene expression in individuals with low folate status. We also determined the influence of MTHFR 677C&gt;;T on these outcomes. 20 men homozygous for the variant allele of MTHFR and 20 men without the polymorphism, aged 45–65, whose average plasma folate was 10.53 nmol/L were selected for the study from Milan, Italy. The subjects were randomized to receive placebo or 400μg folic acid tablets. Blood samples were collected before and after 12 weeks of supplementation. When compared to subjects on placebo, those who received folic acid had higher folate concentration (9.78 nmol/L vs 44.56 nmol/L, P&lt;0.0001) and lower homocysteine concentration (12.59 μmol/L vs 9.05 μmol/L, P=0.1) in plasma at the end of 12 weeks. Changes in gene expression in leukocytes were determined by microarray analysis. Expression of multiple genes for pro‐inflammatory chemokines and interleukins decreased with folic acid supplementation, especially in TT genotypes of MTHFR. Folic acid supplementation at current RDA can potentially alter inflammation in individuals with low folate status. Supported by USDA grant 2005–35200‐15296 &amp; USDA cooperative agreement 51520–008‐04S.

Seasonal Folate Serum Concentrations at Different Nutrition

Folic acid (vitamin B9) rich sources are leafy green vegetables, legumes, whole grains, egg yolk, liver, and citrus fruit. In winter and early spring, there could be insufficient supply of vegetables and fruit and thus lower intake of folic acid and possible deficient folic acid blood concentrations. The aim of the study was to assess serum vitamin B9 concentrations depending on the season (the last third of winter - March, the last third of spring - May/June and the beginning of autumn - September) and different nutritional habits (apparently healthy adults non-smoking, non-obese 366 subjects; 204 persons of general population on traditional mixed diet; and 162 long-term lacto-ovo vegetarians). In general population group, the mean concentration of folate in March was low (narrowly above lower reference limit) with high incidence of deficient values - 31.5%. In May/ June vs. March was folate concentration significantly higher with deficient values in 13.2% of individuals. The highest serum values were observed in September with 11.1% of deficient values. In vegetarian vs. non-vegetarian group, significantly higher folate concentrations were found in each season with no deficient values. Folate and vitamin B12 are the regulators of homocysteinemia; plant food lacks of vitamin B12. The deficient folate serum values in March caused the mild hyperhomocysteinemia in 12.3% of individuals vs. only 5.9% and 4.8% of subjects in groups investigated in May/June and September. In spite of high folate concentrations in all investigations and no deficient value, 19.6-22.8% of vegetarians suffer from mild hyperhomocysteinemia as a consequence of deficient vitamin B12 concentrations in one quarter of subjects. As far as the general population is concerned, our findings suggest that winter and early spring are critical seasons in regards to optimal serum folate concentrations.

Folic acid enforces DNA methylation-mediated transcriptional silencing of PTEN, APC and RARbeta2 tumour suppressor genes in breast cancer

Folate, one of the most studied dietary compounds, has recently become the main topic of debates on food fortification. Although low folate levels may be associated with increased risk of cancer development, simultaneously several reports indicate a detrimental effects mediated by high folate concentrations. Using the methylation sensitive restriction analysis (MSRA) and real-time RT-PCR we tested the effect of folic acid on DNA promoter methylation and expression of PTEN, APC and RARbeta2 tumour suppressor genes in MCF-7 and MDA-MB-231 breast cancer cell lines with different invasive capacity. The tested genes encode proteins involved in regulation of oncogenic intracellular signaling pathways. The results show that the increasing concentrations of folic acid lead to a dose-dependent down-regulation of tumour suppressor genes which may be linked to the increased DNA methylation detected within their promoter regions. The effects were more remarkable in non-invasive MCF-7 cells where we also observed 30% up-regulation of DNMT1 expression at the highest folate concentration used. Our findings show that caution need to be used when introducing folic acid supplementation since it may lead to cancer progression.

High homocysteine and low folate concentrations in acute aortic dissection

BackgroundBiomarkers for monitoring progression and prognosis of thoracic aneurysm are of great interest. Homocysteine (Hcy) induces elastolysis in arterial media and may directly affect fibrillin-1 or collagen whereas lipoprotein (Lp) (a) inhibits elastolysis by reducing activation of matrix metallopeptidase-9. MethodsWe studied 31 consecutive patients with acute aortic dissection (AAD) admitted for emergency surgery (group I, 60±13years old, 25 men), 30 consecutive patients with chronic aneurysms of the ascending aorta (group II, 67±12years old, 24 men) and 20 healthy controls (group III, 58±15years old, 14 men). We evaluated Hcy, folate, B12, Lp(a) and methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism at baseline. ResultsHcy, folate and B12 differed significantly among the 3 studied groups (P=0.016, P=0.004 and P=0.001, respectively). The levels of Hcy and B12 were significantly higher in group I compared to both groups II and III (P=0.05 and P=0.002, P<0.001 and P=0.017, respectively) and without significant differences between groups II and III (P=0.083 and P=0.124). Folate was significantly lower in group I compared to both groups II and III (P=0.001 and P=0.006, respectively) and without marked difference between groups II and III (P=0.409). No significant difference was found in serum levels of Lp (a) (P=0.074) or among the frequency of MTHFR C677T genotypes. ConclusionsPatients with AAD present with higher Hcy and lower folate compared to both chronic aneurysms and controls.