Marker Of Folate Status Research Articles

Folate intake, markers of folate status and oral clefts: an updated set of systematic reviews and meta-analyses

Rationale: There has been a longstanding debate about the role of folate in the etiology of orofacial clefts (OFCs). The aim of the present work is to update the knowledge synthesis published over a decade ago and to bring together different types of evidence.

Homocysteine metabolism and the associations of global DNA methylation with selected gene polymorphisms and nutritional factors in patients with dementia

Epigenetics (particularly DNA methylation) together with environmental and genetic factors, are key to understanding the pathogenesis of many diseases including dementia. Disturbances in DNA methylation have already been implicated in dementia. Homocysteine metabolism, with folate and vitamin B12 as essential cofactors, is integral to methylation processes.We evaluated in a case-control study the association of global DNA methylation, homocysteine, folate and vitamin B12 status with dementia. Selected polymorphisms of genes previously associated with dementia development and the influence of various factors on DNA methylation were also investigated.102 patients with dementia (53 with Alzheimer's disease, 17 with vascular dementia and 32 with mixed dementia) were recruited. The non-demented controls consisted of 45 age-matched subjects without dementia and 47 individuals with mild cognitive impairment. Global DNA methylation was determined by Imprint Methylated DNA Quantification Kit MDQ1 (Sigma-Aldrich, Gillingham, Dorset, UK). Plasma homocysteine, serum folate and vitamin B12 were determined by chemiluminescence. Plasma and erythrocyte 5-methyltetrahydrofolate and plasma methylmalonic acid (markers of folate and vitamin B12 status) were measured by HPLC. APOE, PON1 p.Q192R, MTHFR 677C>T (c.665C>T) and IL1B-511C>T polymorphisms were identified using PCR-RFLP methods.Patients with dementia had significantly higher concentrations of homocysteine (p=0.012) and methylmalonic acid (p=0.016) and lower folate (p=0.002) and plasma 5-methyltetrahydrofolate (p=0.005) than non-demented subjects. There was no difference in DNA methylation between patients and controls. A non-significant tendency to higher DNA methylation in patients with vascular dementia (p=0.061) was observed. Multivariate regression analysis of all recruited individuals demonstrated a significant positive association between DNA methylation and folate (p=0.013), creatinine (p=0.003) concentrations and IL1B-511T (p=0.002) and PON1 192R (p=0.049) alleles and negative association with fasting glucose (p=0.004).The biochemical results showed significantly lower folate and vitamin B12 status in demented patients than controls. Global DNA methylation was associated with markers of folate status, creatinine, glucose and PON1 and IL1B polymorphisms.

Post-hatching ontogeny of intestinal proton-coupled folate transporter and reduced folate carrier in broiler chickens

Folate transporters, including the reduced folate carrier and the proton-coupled folate transporter, encoded by Slc19a1 and Slc46a1 genes respectively, play important roles in the transport of folate across biological membranes given the hydrophilic nature of folates. Although a number of studies have demonstrated that these two transporters are regulated ontogenetically in mammals, little data are available on their developmental patterns of expression in poultry. The objective of this study was to investigate the expression patterns of Slc19a1 and Slc46a1 in jejunal and cecal tissue of broiler chickens during post-hatching development. Post-hatch male chicks (Ross × Ross) had free access to water and a soybean/wheat-based diet. Jejunal, cecal and blood samples were collected on day-of-hatch but before feeding (D0), and on D2, D7, D14, D21 and D35 post-hatch (n = 8 at each time point), respectively. Plasma folate concentrations were low on the day of hatch and increased with maturation; by contrast, plasma homocysteine, a marker of folate status, was highest (P < 0.05) in the day-of-hatch birds and decreased thereafter. Increasing age reduced mRNA abundance of Slc19a1 (P < 0.05) in the jejunum and cecum. Abundance of Slc46a1 mRNA (P < 0.05) gradually decreased in the cecum with increasing age and that of Slc46a1 in the jejunum initially decreased and then increased to level similar to that of day-of-hatch. The study provides some initial data on ontogenetic regulation of Slc19a1 and Slc46a1 in the jejunum and cecum of the chicken and lays the ground work for future nutritional studies. Moreover, the expression of Slc19a1 and Slc46a1 transcripts in the cecum provides evidence of the potential for cecally derived folate to contribute to the folate status of the host.

Systemic folate status, rectal mucosal folate concentration and dietary intake in patients at differential risk of bowel cancer (The FAB2 Study)

Folate has been strongly implicated in the aetiology of colorectal cancer. However, the relationship between dietary folate intake, rectal mucosal folate status and colorectal cancer risk is uncertain. The study aimed to estimate nutrient intakes and measure systemic folate status and rectal mucosal folate concentration in people at differential risk of developing colorectal cancer. Two hundred and twenty-eight individuals were recruited from gastroenterology clinics and subdivided into three patient groups: untreated colorectal cancer (n = 43), adenomatous polyps (n = 90) or normal bowel (n = 95). Biopsies from macroscopically normal rectal mucosa and blood were collected and used for the measurement of rectal mucosal 5-methyltetrahydrofolate (5-MeTHF) and systemic markers of folate status, respectively. Nutrient intake was estimated using a validated food frequency questionnaire. Dietary intake variables, plasma 5-MeTHF and red cell folate and plasma homocysteine concentrations were similar in all three subject groups and 95% CI fell within normal range for each variable. Rectal mucosal 5-MeTHF concentration was higher in the normal mucosa of adenomatous polyp patients than in normal subjects (P = 0.055). Rectal mucosal 5-MeTHF was associated significantly with plasma folate (P < 0.001, r = 0.294), red cell folate (P = 0.014, r = 0.305), plasma homocysteine (P = 0.017, r = -0.163) and dietary folate intake (P = 0.036, r = 0.152). This study demonstrates adequate folate status of patients attending gastroenterology clinics for the investigation of bowel symptoms, with no significant difference in dietary intakes or systemic folate status indices according to diagnosis. Rectal mucosal 5-MeTHF concentrations were elevated in adenomatous polyp patients, but failed to reach significance. Further studies are required to determine the biological significance of this observation.

Folate intake and markers of folate status in women of reproductive age, pregnant and lactating women: a meta-analysis.

Background. Pregnant and breastfeeding women are at risk for folate deficiency. Folate supplementation has been shown to be associated with enhanced markers of folate status. However, dose-response analyses for adult women are still lacking. Objective. To assess the dose-response relationship between total folate intake (folic acid plus dietary folate) and markers of folate status (plasma/serum folate, red blood cell folate, and plasma homocysteine); to evaluate potential differences between women in childbearing age, pregnant and lactating women. Methods. Electronic literature searches were carried out on three databases until February 2010. The overall pooled regression coefficient (β) and SE(β) were calculated using meta-analysis on a double-log scale. Results. The majority of data was based on nonpregnant, nonlactating women in childbearingage. The pooled estimate of the relationship between folate intake and serum/plasma folate was 0.56 (95% CI = 0.40–0.72, P < 0.00001); that is, the doubling of folate intake increases the folate level in serum/plasma by 47%. For red blood cell folate, the pooled-effect estimate was 0.30 (95% CI = 0.22–0.38, P < 0.00001), that is, +23% for doubling intake. For plasma-homocysteine it was –0.10 (95% = –0.17 to –0.04, P = 0.001), that is, –7% for doubling the intake. Associations tended to be weaker in pregnant and lactating women. Conclusion. Significant relationships between folate intake and serum/plasma folate, red blood cell folate, and plasma homocysteine were quantified. This dose-response methodology may be applied for setting requirements for women in childbearing age, as well as for pregnant and lactating women.

Homocysteine and Folate Status in an Era of Folic Acid Fortification: Balancing Benefits, Risks, and B-vitamins

Mandatory folic acid (vitamin B9) fortification of flour products to a level of 140–150 μg/100g was implemented in the US and Canada in 1998. The rationale was to improve folate status in women of childbearing age and thereby decrease the incidence of neural tube defects (NTDs). Studies with complete ascertainment of prenatally diagnosed NTD cases indicate that fortification has prevented up to 50% of NTDs(1). Fortification has therefore been highly successful in achieving its primary objective. Folate concentration in serum and erythrocytes is a marker of folate status, which is inversely associated with the plasma concentration of total homocysteine (tHcy). Cobalamin (vitamin B12) status and renal function are also strong determinants of plasma tHcy(2), and moderate hyperhomocysteinemia is associated with an increased risk of chronic diseases, including cardiovascular disease, dementia, and impaired cognition(3). In this issue of Clinical Chemistry , Pfeiffer and colleagues(4) report on concentrations of tHcy in approximately 26 000 participants in the National Health and Nutrition Examination Survey (NHANES) from 1991 through 1994, and from 3 postfortification surveys (1999–2004). When comparing the postfortification to the prefortification period, Pfeiffer and colleagues found a tHcy decrease of approximately 10%, and a pronounced decrease in the prevalence of individuals with elevated tHcy (>13 μmol/L). These observations complement recent data published by the same authors, which demonstrate an increase in serum and erythrocyte folates, and no change in serum cobalamin in NHANES samples during the same time period(5). Results from these recent studies by Pfeiffer et al. confirm previous studies on folate and homocysteine in NHANES(6)(7) and the Framingham cohort(8). A slight decrease in blood folate between the first (1999–2000) and third (2003–2004) postfortification periods(5 …

Are Encephaloceles Neural Tube Defects?

Encephalocele is classified as a neural tube defect, but questions have been raised regarding whether its epidemiological characteristics are similar to those of other neural tube defects. We compared characteristics of temporal trends in, and the impact of folic acid grain fortification on, the prevalence of encephalocele, spina bifida, and anencephaly using data from the Metropolitan Atlanta Congenital Defects Program, a population-based birth defects surveillance system. Prevalences of encephalocele, spina bifida, and anencephaly were compared by maternal age, gender, race, birth weight, ascertainment period (1968-1981, 1982-1993, or 1994-2002), and fortification period (1994-1996 [prefortification] and 1998-2002 [postfortification]) using prevalence ratios with 95% confidence intervals. Temporal trends were assessed using Poisson and negative binomial regression models. Prevalence rates of encephalocele (n = 167), spina bifida (n = 650), and anencephaly (n = 431) were 1.4, 5.5, and 3.7 per 10 000 live births, respectively. Encephalocele was similar to anencephaly in showing an increased prevalence among girls and multiple gestation pregnancies and to spina bifida and anencephaly in an annual prevalence decrease between 1968 and 2002 (-1.2% for encephalocele, -4.2% for spina bifida, and -3.6% for anencephaly). With fortification, prevalence decreased for spina bifida but not significantly for encephalocele or anencephaly. Encephalocele shows more similarities to spina bifida or anencephaly than it shows differences with respect to characteristics, temporal trend, and impact of fortification. Additional studies should be done to explore the etiologic heterogeneity of encephalocele using better markers of folate status and a wider range of risk factors.

Relationship Between Plasma and Dietary Markers of Folate Status and Bone Mineral Density

Relationship Between Plasma and Dietary Markers of Folate Status and Bone Mineral Density

DNA replication biomarkers as functional markers of folate status in colon cells

DNA replication biomarkers as functional markers of folate status in colon cells

Plasma folate as marker of folate status in epidemiological studies: the European Investigation into Cancer and Nutrition (EPIC)-Potsdam study.

Folate deficiency is often discussed as a potential risk factor for CVD and some cancers. Reliable assessment of folate status in large-scale epidemiological studies is therefore of major importance. The present study assessed the value of plasma folate (PF) compared with erythrocyte folate (EF) as a marker of folate status in 363 participants in the European Investigation into Cancer and Nutrition (EPIC)-Potsdam cohort. EF and PF, total homocysteine (tHcy), pyridoxine, cobalamin, creatinine, total protein and packed cell volume were determined; glutamate carboxypeptidase (GCP) C1561T, reduced folate carrier (RFC) G80A and methylenetetrahydrofolate (MTHFR) C677T polymorphisms were analysed. Anthropometric measurements were taken and dietary intake was assessed with the EPIC-Potsdam food-frequency questionnaire. Comparison of EF and PF with factors that may modulate their concentrations was performed. Cross-classification of blood folates in quintile categories resulted in correct classification into the same or adjacent category of 75.5 % of all subjects. Age, BMI, pyridoxine and cobalamin, fruit and vegetable intake, and vitamin supplementation 24 h before blood draw were positively associated with EF and with PF. For tHcy an inverse association was found. Participants with the MTHFR 677TT genotype showed significantly elevated EF concentrations compared with those with 677CT genotype; EF and PF were more strongly correlated (r 0.78, P<0.0001) for participants with MTHFR 677TT genotype than for those with the 677CC or 677CT genotype. In summary, our present results indicate that plasma folate seems to be a suitable marker for assessment of folate status for use in large-scale epidemiological studies.

Folate Status in Germany 1997–2000

Data about folate intake and blood values of the German population, published between 1997 and 2000, have been reviewed. Median folate intake is about 250 micrograms/day in the adult population, which indicates a high likelihood of inadequate intake when compared to the Estimated Average Requirement (EAR) of 320 micrograms/day. Only a few studies have evaluated serum and erythrocyte folate or plasma homocysteine as a marker of folate status. The most representative data show that 25% of German women of childbearing age have an inadequate recent folate intake. Only 13.3% of the women have red blood cell folate values above the critical value of 400 micrograms/day established by Daly et al (1995). Folic acid fortification of food is shown to be responsible for about 25% of folate intake in the German child and adolescent population in one study. If we extrapolate these data to the general population, folic acid fortification could be the explanation for the differences observed between folate intake and blood values. The discrepancy might also be explained by slight inaccuracies in food composition tables. Folate intake from fortified food or from supplements is not taken into account in most of the studies, which is a variable that can lead to confusion. Nutrition surveys should adapt official composition tables for local food patterns, and include fortified commercial foods, in order to make folate intake data more accurate. However, representative serum and erythrocyte folate values are lacking for most age groups. Before taking public health measures concerning folate fortification of food, the real folate status of the German population should be established.

The use of biomarkers in multicentric studies with particular consideration of iodine, sodium, iron, folate and vitamin D.

To determine which biomarkers should be used in a European monitoring system to assess intake of iodine, sodium, iron, folate and vitamin D. These nutrients are relevant for human health but difficult to assess in the diet in a comparable way among countries. Iodine and sodium are mainly excreted in urine. Mean population intakes of iodine and sodium can be estimated by casual urine samples. However, habitual individual intake assessments require multiple 24 h urine collections. Serum ferritin is a sensitive test of iron status (mobilizable storage iron) and continues to be the leading single determination for individual iron status, but with serum transferrin receptor as a promising alternative because it is more specific than ferritin. Erythrocyte folate and homocysteine in blood are markers of folate status which are able to discriminate between normal status and levels of insufficiency in an individual. Serum 25-hydroxyvitamin D is a good marker for vitamin D deficiency in the individual, and can distinguish between overt deficiency and marginal deficiency, especially if combined with serum parathyroid hormone. Specific and sensitive markers for the dietary intake of iodine, sodium, iron, folate and vitamin D are available, which have the advantage of being more accurate than intake estimations derived from dietary surveys. However, the use of biomarkers also has disadvantages such as extra burden in terms of logistics, budget and ethical approval, and can moreover reduce the participation rate. More basic data for the validity of cross-country comparisons are needed and ideas in terms of study design and sampling frame.

Erythrocyte Folate Does Not Accurately Reflect Folate Status in Sickle Cell Disease

Optimal folate status of sickle cell disease (SCD) patients might be important because these patients have an inherent high risk of endothelial damage. Serum folate, erythrocyte folate, and plasma homocysteine are used as static and functional markers of folate status. We recently investigated the folate status of SCD patients (1) and subsequently established the dosages needed for optimal daily supplementation (Van der Dijs et al., submitted for publication). The daily intakes were progressively increased during 70 weeks. During dose escalation, we observed different responses for red blood cell (RBC) folate, but not serum folate, in hemoglobin SS (HbSS) and HbSC patients. These subgroups did not differ in RBC folate at baseline, but the folate concentrations of HbSS patients increased to reach a higher steady state after supplementation. Steady-state …

Plasma total homocysteine, pregnancy complications, and adverse pregnancy outcomes: the Hordaland Homocysteine Study

Total homocysteine (tHcy) measured in serum or plasma is a marker of folate status and a risk factor for cardiovascular disease. Our objective was to investigate associations between tHcy and complications and adverse outcomes of pregnancy. Plasma tHcy values measured in 1992-1993 in 5883 women aged 40-42 y were compared with outcomes and complications of 14492 pregnancies in the same women that were reported to the Medical Birth Registry of Norway from 1967 to 1996. When we compared the upper with the lower quartile of plasma tHcy, the adjusted risk for preeclampsia was 32% higher [odds ratio (OR): 1. 32; 95% CI: 0.98, 1.77; P for trend = 0.02], that for prematurity was 38% higher (OR: 1.38; 95% CI: 1.09, 1.75; P for trend = 0.005), and that for very low birth weight was 101% higher (OR: 2.01; 95% CI: 1.23, 3.27; P for trend = 0.003). These associations were stronger during the years closest to the tHcy determination (1980-1996), when there was also a significant relation between tHcy concentration and stillbirth (OR: 2.03; 95% CI: 0.98, 4.21; P for trend = 0.02). Neural tube defects and clubfoot had significant associations with plasma tHcy. Placental abruption had no relation with tHcy quartile, but the adjusted OR when tHcy concentrations >15 micromol/L were compared with lower values was 3.13 (95% CI: 1.63, 6. 03; P = 0.001). Elevated tHcy concentration is associated with common pregnancy complications and adverse pregnancy outcomes.

Folate–Homocysteine Interrelations: Potential New Markers of Folate Status

We report a transient drop in plasma Hcy and Cys following a single oral dose of PteGlu. The thiol change was concomitant with both the peak plasma 5CH3H4PteGlu1level (by HPLC) and the maximum plasmaLactobacillus caseiactivity which reflects absorption of unmodified PteGlu. The significant reciprocal association of Hcy with radioassay RBC folate (r= −0.28, 99% CI −0.48, −0.05,P= 0.0016), serum folate (r= −0.37, 99% CI −0.56, −16,P= 0.0001), and vitamin B12(r= −0.42, 99% CI −0.59, −21,P= 0.0001) is shown and reflects the long-term nutritional effect of B vitamins on this important, potentially atherogenic thiol. These are now well-established associations. We extend the potential for investigation of folate metabolism in health and disease by evaluating a range of new folate indices which are based on erythrocyte coenzymes. These have been looked at independently and in association with established parameters. Erythrocyte methylfolates (mono- to hexaglutamate-5CH3H4PteGlu1–6), formylfolates (tri- to pentaglutamate-5CHOH4PteGlu3–5),formiminotetrahydrofolate (formiminoH4PteGlu1), unsubstituted tetrahydrofolate (H4PteGlu1), andpara-aminobenzoylglutamate (P-ABG) have been measured by HPLC with fluorescence detection. A positive linear association exists between (i) H4PteGlu1and radioassay RBC folate (r= 0.50, 99% CI 0.07, 0.77,P= 0.0036), and (ii) H4PteGlu1and tetraglutamates of both formyl- and methylfolate (r= 0.52, 99% CI 0.10, 0.78,P= 0.0022, andr= 0.56, 99% CI 0.15, 0.80,P= 0.0009, respectively). Since, in addition, a reciprocal linear association exists between Hcy and tetraglutamyl formylfolate (r= −0.41, 99% CI −0.73, 0.05,P= 0.0206), erythrocyte tetraglutamates may be a good reflection of the bodies' active coenzyme pools. Pentaglutamyl formylfolate, the longest oligo-γ-glutamyl chain form of this coenzyme may be a good indicator of folate depletion. The abundance of this coenzyme both increases with increasing Hcy (r= 0.55, 99% CI 0.13, 0.80,P= 0.0014) and increases as H4PteGlu1, the principle folate congener, decreases (r= −0.59, 99% CI −0.82, −0.20,P= 0.0004). Furthermore, the apparent equilibrium between substrate (5CH3H4PteGlu1) and product (H4PteGlu1) of methionine synthase is significantly associated with the abundance of 5CHOH4PteGlu5(r= −0.53, 99% CI −0.79, −0.11,P= 0.0018). This suggests that low methionine synthase activity for whatever reason (metabolic or dietary) may lead to an increase in the relative abundance of 5CHOH4PteGlu5. Like 5CHOH4PteGlu5, evidence is given that 5CH3H4PteGlu6, the longest oligo-γ-glutamyl chain form of this particular coenzyme pool, may also be a good indicator of folate depletion. This is shown by a change in the relative proportion of erythrocyte methylfolate polyglutamates following supplementation with 400 μg/day PteGlu. Short-chain polyglutamates of methylfolate (5CH3H4PteGlu1→ 5CH3H4PteGlu4) increase in proportion to the total methylfolate pool, while long-chain polyglutamates of methylfolate (5CH3H4PteGlu5and particularly 5CH3H4PteGlu6) decrease in their relative abundance.

Nutritional Epidemiology of Cervical Neoplasia

There appears to be a natural progression of some preinvasive cervical lesions to more advanced lesions. Although research has evaluated the associations between nutrients and particular preinvasive lesions or invasive disease, little work has been done to compare results across the spectrum of lesions in the progression to invasive disease. This review compiles studies that have evaluated the relation between nutrients and cervical neoplasia and evaluates the general consistency of the literature across stage of disease. Preformed vitamin A does not appear to be related to risk of any preinvasive or invasive lesions, whereas vitamin C has been associated with a reduced risk for dysplasia, in situ cancer, and invasive disease, particularly among smokers. There was evidence of reduced risks associated with various carotenoids and vitamin E at all stages of the disease process, although these studies were inconsistent and further work is needed. Folate was the only nutrient that appeared to be protective for dysplastic lesions and not related to risk of in situ or invasive disease. Red blood cell folate was a better predictor of dysplasia than were serum or dietary folate, and further investigation using this marker of folate status is warranted. Research is needed across a spectrum of lesions within one study, with particular attention to interactions between nutrients and other risk factors for disease.