Low Folate Status Research Articles

Serum homocysteine levels of retinal vein occlusion patients with different ages and types

Objective To observe serum homocysteine (Hcy) levels in retinal vein occlusion (RVO) patients with different ages and types. Methods A total of 79 patients (79 eyes) diagnosed with RVO were enrolled. There were 33 females and 46 males, the mean age was (57.00±9.29) years. Eighty-two age- and sex-matched patients (82 eyes) without retinal vascular disease were included as controls. There were 32 females and 50 males, the mean age was (60.00±10.15) years. Among RVO patients, there were 24 patients younger than 50 years old (young patients) and 55 patients older than 50 years old (elderly patients); 35 patients with central RVO (CRVO) and 44 patients with branch RVO (BRVO). Fasting plasma Hcy, serum vitamin (Vit) B6, B12 and folate levels were measured in all patients. The relationship of high Hcy, low VitB6, low folate and RVO with different age were analyzed. Results Hcy level was significantly higher in RVO patients than control subjects (t=2.946, P 0.05). Concentrations of Hcy, folate, VitB12 and VitB6 were not different between patients with CRVO and BRVO (t=0.756, 1.306, 0.682, 1.306; P>0.05). Hcy level was significantly higher in the young RVO patients than in the elderly RVO patients (t=2.394, P 0.05). The number of patients with high Hcy[χ2=13.67, odds ratio (OR)=3.327, 95% confidence interval (CI)=1.742 - 6.354], low VitB6 (χ2=5.28, OR=2.068, 95%CI=1.103 - 3.878) and low folate status (χ2=8.642, OR=2.546, 95%CI=1.349 - 4.806) in RVO patients were more than control subjects (P=0.0001, 0.023, 0.004). Conclusions High Hcy, low folate and low VitB6 were risk factors for the onset of RVO. Hcy may play more important role in young patients with RVO. Hcy, folate and VitB6 levels were similar in CRVO and BRVO patients. Key words: Retinal vein occlusion/etiology; Homocysteine; Folic acid deficiency/ complications; Vitamin B 6 deficiency/complications

Folic Acid Supplementation in Postpolypectomy Patients in a Randomized Controlled Trial Increases Tissue Folate Concentrations and Reduces Aberrant DNA Biomarkers in Colonic Tissues Adjacent to the Former Polyp Site

Background: Low folate status is associated with an increased risk of colorectal carcinogenesis. Optimal folate status may be genoprotective by preventing uracil misincorporation into DNA and DNA hypomethylation. Adenomatous polyps have low folate status compared with normal colonic mucosa, and they are surrounded by histologically normal mucosa that also is of low folate status.Objective: In a randomized controlled trial conducted at a single Dublin hospital between April 2002 and March 2004, we assessed the effect of folic acid supplementation on tissue folate, uracil misincorporation into DNA, and global DNA hypomethylation in colonocytes isolated from sites of adenomatous polyps and from histologically normal tissue adjacent and 10–15 cm distal to them.Methods: Twenty patients with adenomatous polyps on initial colonoscopy and polypectomy were randomly assigned to receive either 600 μg folic acid/d [n = 12, 38% men, mean age 64.3 y, and body mass index (BMI, in kg/m2) 26.6] or placebo (n = 8, 50% men, mean age 68.4 y, and BMI 27.2) for 6 mo, and then repeat the colonoscopy. Blood and colonocyte tissue folate concentrations were measured with the use of a microbiological assay. Uracil misincorporation and global DNA hypomethylation were measured in colonocytes with the use of modified comet assays.Results: Over time, folic acid supplementation, compared with placebo, increased tissue folate (mean ± SEM) from 15.6 ± 2.62 pg/105 cells to 18.1 ± 2.12 pg/105 cells (P < 0.001) and decreased the global DNA hypomethylation ratio from 1.7 ± 0.1 to 1.0 ± 0.1 (P < 0.001). The uracil misincorporation ratio decreased by 0.5 ± 0.1 for the site adjacent to the polyp over time (P = 0.05).Conclusion: A response to folic acid supplementation, which increased colonocyte folate and improved folate-related DNA biomarkers of cancer risk, was seen in the participants studied. Exploratory analysis points toward the area formerly adjacent to polyps as possibly driving the response. That these areas persist after polypectomy in the absence of folate supplementation is consistent with a potentially carcinogenic field’s causing the appearance of the polyp.

Predictors of folate status among pregnant Japanese women: the Hokkaido Study on Environment and Children's Health, 2002-2012.

The International Clearinghouse for Birth Defects, Surveillance and Research reports a rise in the prevalence rate of spina bifida in Japan. We determined first-trimester folate status of Hokkaido women and identified potential predictors. Participants were 15 266 pregnant women of the Hokkaido Study on Environment and Children's Health Cohort. Data were extracted from self-reported questionnaires and biochemical assay results. Demographic determinants of low folate status were younger maternal age (adjusted OR (AOR) 1·48; 95 % CI 1·32, 1·66), lower educational level (AOR 1·27; 95 % CI 1·17, 1·39) and lower annual income (AOR 1·11; 95 % CI 1·01, 1·22). Plasma cotinine concentrations of 1·19-65·21 nmol/l increased the risk of low folate status (AOR 1·20; 95 % CI 1·10, 1·31) and concentrations >65·21 nmol/l further increased the risk (AOR 1·91; 95 % CI 1·70, 2·14). The most favourable predictor was use of folic acid (FA) supplements (AOR 0·19; 95 % CI 0·17, 0·22). Certain socio-demographic factors influence folate status among pregnant Japanese women. Modifiable negative and positive predictors were active and passive tobacco smoking and use of FA supplements. Avoiding both active and passive tobacco smoking and using FA supplements could improve the folate status of Japanese women.

Early pregnancy B vitamin status, one carbon metabolism, pregnancy outcome and child development.

Periconception supplementation with folic acid is recommended until 12 gestational weeks to prevent neural tube defects. Doses of folic acid contained in supplements and timing and length of use during pregnancy vary. The effects of status in periconception and pregnancy folate, cobalamin, betaine and their interactions on one carbon metabolism (1C), as well as the global effect of 1C on foetal growth and pregnancy outcome, are reviewed. Results from prospective studies are reviewed. Cessation of folic acid supplement use after the first trimester is associated with a sharp drop in plasma folate status and enhanced conversion of betaine to dimethylglycine. Dimethylglycine production is also higher in mothers with low folate status than in those with normal-high folate status. The effects of high doses of folic acid on one carbon metabolism in mothers with low early pregnancy cobalamin status and on foetal growth are also reviewed. Several studies report that moderately elevated early pregnancy fasting plasma total homocysteine (tHcy) is inversely associated with birth weight and a predictor of intrauterine growth retardation. There is also evidence for increased risk of preterm birth when maternal folate status is low.

Associations of maternal folic acid supplementation and folate concentrations during pregnancy with foetal and child head growth: the Generation R Study

PurposeFolic acid supplementation during pregnancy has been associated with a reduced risk of common neurodevelopmental delays in the offspring. However, it is unclear whether low folate status has effects on the developing brain. We evaluated the associations of maternal folic acid supplementation and folate concentrations during pregnancy with repeatedly measured prenatal and postnatal head circumference in the offspring.MethodsWithin a population-based prospective cohort, we measured maternal plasma folate concentrations at approximately 13 weeks of gestation (90 % range 10.5–17.2) and assessed folic acid supplementation by questionnaire (2001–2005). Up to 11 repeated measures of head circumference were obtained during foetal life (20 and 30 weeks of gestation) and childhood (between birth and age 6 years) in 5866 children (2002–2012).ResultsIn unadjusted models, foetal head growth was 0.006 SD (95 % CI 0.003; 0.009, P < 0.001) faster per week per 1-SD higher maternal folate concentration. After adjustment for confounders, this association was attenuated to 0.004 SD per week (95 % CI 0.000; 0.007, P = 0.02; estimated absolute difference at birth of 2.7 mm). The association was independent of overall foetal growth. No associations were found between maternal folate concentrations and child postnatal head growth. Preconceptional start of folic acid supplementation was associated with larger prenatal head size, but not with prenatal or postnatal head growth.ConclusionsOur results suggest an independent, modest association between maternal folate concentrations in early pregnancy and foetal head growth. More research is needed to identify whether specific brain regions are affected and whether effects of folate on foetal head growth influence children’s long-term functioning.

The impact of MTHFR 677 C/T genotypes on folate status markers: a meta-analysis of folic acid intervention studies.

Methylenetetrahydrofolate reductase (MTHFR) is a key folate pathway enzyme with the T variant of the MTHFR gene increasing the risk of low folate status, particularly coupled with low folate intake. As genetic variability of MTHFR influences folate status, it is important to ensure an adequate intake that overrides genetic effects but minimises any adverse effects. Our aim was to assess the influence of MTHFR genotype on folate status followed by response to supplementation. We performed a meta-analysis of ten folate intervention studies to assess the degree to which MTHFR C677T genotype influenced plasma homocysteine and serum folate levels as measures of folate status. We then examined response after supplementation at intake values up to the upper tolerable limit. The MTHFR 677TT genotype was associated with higher plasma homocysteine (2.7μmol/L, TT vs. CT/CC; 2.8μmol/L, TT vs. CC) and lower serum folate (2.5nmol/L, TT vs. CT/CC; 3.6nmol/L, TT vs. CC). In two studies, the TT groups had mean plasma Hcy>15μmol/L. Serum folate levels were >7nmol/L for all genotype groups. After supplementation of 400 up to 1670μg DFEs of folic acid or folic acid+fortified foods and/or natural food folates for a minimum of 4weeks, there were no significant differences in plasma homocysteine levels; however, individuals with the TT genotype had a lower serum folate response to supplementation (7.2nmol/L, TT vs. CT/CC; 8.7nmol/L, TT vs. CC). This meta-analysis confirms observations from observational and intervention studies that MTHFR TT genotype is associated with increased plasma homocysteine and lowered serum folate and less response to short-term supplementation. The results can be used for modelling and guiding personalised intake recommendations for the nutrient folate.

Joint associations of folate, homocysteine and MTHFR, MTR and MTRR gene polymorphisms with dyslipidemia in a Chinese hypertensive population: a cross-sectional study.

BackgroundDyslipidemia is a well-established risk factor for cardiovascular disease. Serum lipids were affected by several gene polymorphisms, folate, homocysteine and other metabolite levels. We aim to investigate the effects of homocysteine metabolism enzyme polymorphisms (MTHTR C677T, MTHFR A1298C, MTR A2756G and MTRR A66G) and their interactions with folate, homocysteine on serum lipid levels in Chinese patients with hypertension.MethodsParticipants were 480 hypertensive adults that enrolled in September to December 2005 from six different Chinese hospitals (Harbin, Shanghai, Shenyang, Beijing, Xi’an, and Nanjing). Known MTHFR C677T, MTHFR A1298C, MTR A2756G and MTRR A66G genotypes were determined by PCR-RFLP methods. Serum folate was measured by chemiluminescent immunoassay, homocysteine was measured by high-performance liquid chromatography, serum lipids parameters were determined by an automatic biochemistry analyzer, low-density lipoprotein was calculated by Friedewald’s equation. Unitary linear regression model was used to assess the associations of gene polymorphisms, folate and homocysteine on serum lipid profiles. Unconditional logistic regression model was applied to test the interactions of folate, homocysteine and gene polymorphisms on dyslipidemia.ResultsNo correlations between gene polymorphisms and homocysteine on serum lipid profiles. Compared with normal folate patients, patients with low folate showed higher odds of hypertriglyceridemia (OR = 2.02, 95 % CI: 1.25-3.25, P = 0.004) and low levels of high-density lipoprotein cholesterol (OR = 1.88, 95 % CI: 1.07-3.28, P = 0.027). Each of four gene polymorphisms (MTHTR C677T, MTHFR A1298C, MTR A2756G and MTRR A66G) combined with low folate showed higher odds of hypertriglyceridemia (P for trend: 0.049, 0.004, 0.007 and 0.005, respectively). MTHFR C677T and A1298C with low folate showed higher odds of low levels of high-density lipoprotein cholesterol (P for trend: 0.008 and 0.031).ConclusionsLow folate status and homocysteine metabolism gene polymorphisms (MTHTR C677T, MTHFR A1298C, MTR A2756G and MTRR A66G) may have a synergistic effect increased the incidence of dyslipidemia in Chinese hypertensive population.

Heme oxygenase-1 promoter polymorphisms and risk of spina bifida.

Spina bifida is the most common form of neural tube defects (NTDs). Etiologies of NTDs are multifactorial, and oxidative stress is believed to play a key role in NTD development. Heme oxygenase (HO), the rate-limiting enzyme in heme degradation, has multiple protective properties including mediating antioxidant processes, making it an ideal candidate for study. The inducible HO isoform (HO-1) has two functional genetic polymorphisms: (GT)n dinucleotide repeats and A(-413)T SNP (rs2071746), both of which can affect its promoter activity. However, no study has investigated a possible association between HO-1 genetic polymorphisms and risk of NTDs. This case-control study included 152 spina bifida cases (all myelomeningoceles) and 148 non-malformed controls obtained from the California Birth Defects Monitoring Program reflecting births during 1990 to 1999. Genetic polymorphisms were determined by polymerase chain reaction and amplified fragment length polymorphisms/restriction fragment length polymorphisms using genomic DNA extracted from archived newborn blood spots. Genotype and haplotype frequencies of two HO-1 promoter polymorphisms between cases and controls were compared. For (GT)n dinucleotide repeat lengths and the A(-413)T SNP, no significant differences in allele frequencies or genotypes were found. Linkage disequilibrium was observed between the HO-1 polymorphisms (D': 0.833); however, haplotype analyses did not show increased risk of spina bifida overall or by race/ethnicity. Although, an association was not found between HO-1 polymorphisms and risk of spina bifida, we speculate that the combined effect of low HO-1 expression and exposures to known environmental oxidative stressors (low folate status or diabetes), may overwhelm antioxidant defenses and increase risk of NTDs and warrants further study.

Low vitamin B12 and elevated folate status in older adults-a risk factor for cognitive impairment?

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A lower degree of PBMC L1 methylation in women with lower folate status may explain the MTHFR C677T polymorphism associated higher risk of CIN in the US post folic acid fortification era.

BackgroundStudies in populations unexposed to folic acid (FA) fortification have demonstrated that MTHFR C677T polymorphism is associated with increased risk of higher grades of cervical intraepithelial neoplasia (CIN 2+). However, it is unknown whether exposure to higher folate as a result of the FA fortification program has altered the association between MTHFR C677T and risk of CIN, or the mechanisms involved with such alterations. The current study investigated the following in a FA fortified population: 1) The association between MTHFR C677T polymorphism and risk of CIN 2+; 2) The modifying effects of plasma folate concentrations on this association; and 3) The modifying effects of plasma folate on the association between the polymorphism and degree of methylation of long interspersed nucleotide elements (L1s), in peripheral blood mononuclear cell (PBMC) DNA, a documented biomarker of CIN risk.MethodsThe study included 457 US women diagnosed with either CIN 2+ (cases) or ≤ CIN 1 (non-cases). Unconditional logistic regression models were used to test the associations after adjusting for relevant risk factors for CIN.ResultsThe 677CT/TT MTHFR genotypes were not associated with the risk of CIN 2+. Women with CT/TT genotype with lower folate, however, were more likely to be diagnosed with CIN 2+ compared to women with CT/TT genotype with higher folate (OR = 2.41, P = 0.030). Women with CT/TT genotype with lower folate were less likely to have a higher degree of PBMC L1 methylation compared to women with CT/TT genotype with higher folate (OR = 0.28, P = 0.017).ConclusionsThis study provides the first evidence that the MTHFR 677CT/TT genotype-associated lower degree of PBMC L1 methylation increases the risk of CIN 2+ in women in the US post-FA fortification era. Thus, even in the post-FA fortification era, not all women have adequate folate status to overcome MTHFR 677CT/TT genotype-associated lower degree of L1 methylation.

Low folate levels are associated with reduced risk of colorectal cancer in a population with low folate status.

A diet rich in folate is associated with a reduced colorectal cancer risk, whereas the role of circulating levels is less clear. The aim of this study was to relate prediagnostic plasma folate, vitamin B12, and homocysteine concentrations to the risk of colorectal cancer. This was a prospective case-control study of 331 cases and 662 matched controls nested within the population-based Northern Sweden Health and Disease Study. Median follow-up time from recruitment to diagnosis was 10.8 years. Plasma folate concentrations were positively related to colorectal cancer risk; multivariate odds ratios were 1.62 [95% confidence intervals (CI), 1.08-2.42] and 1.42 (95% CI, 0.94-2.21) for the middle and highest versus lowest tertile, respectively. In subjects with follow-up <10.8 years, a statistically significant doubled risk was observed for the middle and highest versus lowest tertile, whereas findings for longer follow-up times were null. A positive risk relationship was also observed for tumor stage III-IV but not I-II. Plasma vitamin B12 concentrations were inversely associated with rectal cancer risk. Homocysteine was not significantly related to colorectal cancer risk. In this population-based, nested case-control study, low plasma folate concentrations were associated with a reduced colorectal cancer risk. This protective role was mainly observed in subjects with higher tumor stage or shorter follow-up time between recruitment and diagnosis. Low circulating folate status may protect against colorectal cancer or suppress progression of preneoplastic or neoplastic lesions. These findings may have relevance for the ongoing debate about mandatory folic acid fortification of flour.

Folic acid supplementation for prevention of mood disorders in young people at familial risk: A randomised, double blind, placebo controlled trial

BackgroundClinical mood disorders often become clinically manifest in the later teenage years and early twenties and can be associated with a poor long-term prognosis. The primary prevention of these disorders would therefore have great public health value. Nutritional supplements are a feasible intervention for primary prevention and several epidemiological studies have indicated links between low folate status and depressive symptomatology in the general population. MethodA randomised, double blind, parallel group, placebo-controlled trial in which participants, aged 14–24 years, at increased familial risk of mood disorder, were randomised to folic acid (2.5mg daily) or identical placebo liquid for a maximum of 36 months. Primary outcome data (the onset of a DSM-IV mood disorder) were collected from 112 participants; 56 per group. ResultsThe incidence of mood disorder in the folic acid and placebo groups were 14.3% and 17.9% respectively, a non-significant difference. However, there was post-hoc evidence that folic acid delayed the time to onset of mood disorder in those participants who became unwell. LimitationsSmall sample size and rate of onset of mood disorders lower than expected. ConclusionsAlthough long term folic acid supplementation was well tolerated, with high levels of adherence, there was no evidence that it reduced the incidence of mood disorder compared to those taking placebo.

Analyses of copy number variation reveal putative susceptibility loci in MTX‐induced mouse neural tube defects

Copy number variations (CNVs) are thought to act as an important genetic mechanism underlying phenotypic heterogeneity. Impaired folate metabolism can result in neural tube defects (NTDs). However, the precise nature of the relationship between low folate status and NTDs remains unclear. Using an array-comparative genomic hybridization (aCGH) assay, we investigated whether CNVs could be detected in the NTD embryonic neural tissues of methotrexate (MTX)-induced folate dysmetabolism pregnant C57BL/6 mice and confirmed the findings with quantitative real-time PCR (qPCR). The CNVs were then comprehensively investigated using bioinformatics methods to prioritize candidate genes. We measured dihydrofolate reductase (DHFR) activity and concentrations of folate and relevant metabolites in maternal serum using enzymologic method and liquid chromatography/tandem mass spectrometry (LC/MS/MS). Three high confidence CNVs on XqA1.1, XqA1.1-qA2, and XqE3 were found in the NTD embryonic neural tissues. Twelve putative genes and three microRNAs were identified as potential susceptibility candidates in MTX-induced NTDs and possible roles in NTD pathogenesis. DHFR activity and 5-methyltetrahydrofolate (5-MeTHF), 5-formyltetrahydrofolate (5-FoTHF), and S-adenosylmethionine (SAM) concentrations of maternal serum decreased significantly after MTX injection. These findings suggest that CNVs caused by defects in folate metabolism lead to NTD, and further support the hypothesis that folate dysmetabolism is a direct cause for CNVs in MTX-induced NTDs.

Folic Acid Supplementation and Interpregnancy Interval

Maternal folic acid supplementation between subsequent pregnancies may be important to reduce the risk of low folate status associated with short interpregnancy intervals. We examined how the prevalence of preconception folic acid use for a given pregnancy in Norwegian women varied according to the time interval from the previous pregnancy. Analysis was based on 48 855 pairs of pregnancies with the second pregnancy included in the Norwegian Mother and Child Cohort Study (birth years 1999-2009). Interpregnancy interval was defined as the time from birth of a child to the conception of the subsequent sibling. Preconception folic acid use was defined as any use of folic acid-containing supplements within the last 4 weeks before the second pregnancy. The prevalence of preconception folic acid use was 31%. Among women with a term birth (≥37 weeks) in the previous pregnancy (92%), those with interpregnancy intervals ≤12 and ≥49 months were associated with up to 35% lower prevalence of preconception folic acid use for the second pregnancy, relative to the reference group (13-24 months). The low use in short intervals was mainly attributable to lower proportion of planned pregnancies and fewer women with higher education. Among women with a preterm birth (<37 weeks) in the previous pregnancy (8%), preconception folic acid use significantly decreased with increasing pregnancy spacing. Our finding of a lower preconception folic acid use in women with both short and long interpregnancy intervals might help identifying those with higher risk of folate deficiency and preventing unwanted pregnancy outcomes.

Is low iron status a risk factor for neural tube defects?

Folic acid supplements can protect against neural tube defects (NTDs). Low folate and low vitamin B12 status may be maternal risk factors for having an NTD affected pregnancy. However, not all NTDs are preventable by having an adequate folate/ B12 status and other potentially modifiable factors may be involved. Folate and vitamin B12 status have important links to iron metabolism. Animal studies support an association between poor iron status and NTDs, but human data are scarce. We examined the relevance of low iron status in a nested NTD case-control study of women within a pregnant population-based cohort. Pregnant women were recruited between 1986 and 1990, when vitamin or iron supplementation in early pregnancy was rare. Blood samples, taken at an average of 14 weeks gestation, were used to measure ferritin and hemoglobin in 64 women during an NTD affected pregnancy and 207 women with unaffected pregnancies. No significant differences in maternal ferritin or hemoglobin concentrations were observed between NTD affected and nonaffected pregnancies (case median ferritin 16.9 µg/L and hemoglobin 12.4 g/dl versus 15.4 µg/L and 12.3g/dl in controls). As reported previously, red cell folate and vitamin B12 concentrations were significantly lower in cases. Furthermore, there was no significant association of iron status with type of NTD lesion (anencephaly or spina bifida). We conclude that low maternal iron status during early pregnancy is not an independent risk factor for NTDs. Adding iron to folic acid for periconceptional use may improve iron status but is not likely to prevent NTDs.

Three-month B vitamin supplementation in pre-school children affects folate status and homocysteine, but not cognitive performance

Suboptimal vitamin B status might affect cognitive performance in early childhood. We tested the hypothesis that short-term supplementation with folic acid and selected B vitamins improves cognitive function in healthy children in a population with relatively low folate status. We screened 1,002 kindergarten children for suboptimal folate status by assessing the total urinary para-aminobenzoylglutamate excretion. Two hundred and fifty low ranking subjects were recruited into a double blind, randomized, controlled trial to receive daily a sachet containing 220 μg folic acid, 1.1 mg vitamin B2, 0.73 mg B6, 1.2 μg B12 and 130 mg calcium, or calcium only for 3 months. Primary outcomes were changes in verbal IQ, short-term memory and processing speed between baseline and study end. Secondary outcomes were urinary markers of folate and vitamin B12 status, acetyl-para-aminobenzoylglutamate and methylmalonic acid, respectively, and, in a subgroup of 120 participants, blood folate and plasma homocysteine. Pre- and post-intervention cognitive measurements were completed by 115 children in the intervention and 122 in the control group. Compared to control, median blood folate increased by about 50% (P for difference, P < 0.0001). Homocysteine decreased by 1.1 μmol/L compared to baseline, no change was seen in the control group (P for difference P < 0.0001) and acetyl-para-aminobenzoylglutamate was 4 nmol/mmol higher compared to control at the end of the intervention (P < 0.0001). We found no relevant differences between the groups for the cognitive measures. Short-term improvement of folate and homocysteine status in healthy children does not appear to affect cognitive performance.

MTHFR C677T genotype and cardiovascular risk in a general population without mandatory folic acid fortification

Meta-analyses have suggested an effect of MTHFR C677T genotype (rs1801133), a proxy for blood total homocysteine, on cardiovascular disease (CVD) in populations with low population dietary folate. The aim was to examine the association and effect modification by serum folate and vitamin B12 levels between MTHFR and CVD-related outcomes in a general population with no mandatory folic acid fortification policy. The study population included 13,748 adults retrieved from pooling of four population-based studies conducted in Denmark. MTHFR genotype, serum folate (measured in approximately 9,356 individuals), and serum vitamin B12 (9,215 individuals), hypertension, and dyslipidemia were measured at baseline, and participants were followed for a mean of 10.5-11.7 years in central registries for diagnoses of stroke (623 incidents), ischaemic heart disease (IHD) (835 incidents), and all-cause mortality (1,272 incidents). The MTHFR genotype (TT vs. CC/CT) was not associated with hypertension [OR (95% CI) 1.09 (0.95-1.25)], dyslipidemia [OR (95% CI) 0.97 (0.84-1.11)], stroke [HR (95% CI) 0.92 (0.69-1.23)], and all-cause mortality [HR (95% CI) 0.94 (0.77-1.14)], either overall, or in participants with low serum folate or B12 status (P values for interactions 0.15-0.94). Individuals with the MTHFR TT genotype had a higher risk of IHD (HR (95% CI) 1.38 (1.11-1.71)), but this association was not modified by folate status (P value for interaction 0.45). Our results do not support a causal relationship between homocysteine and CVD. However, we cannot exclude a direct causal effect of MTHFR C677T genotype on IHD.

Vitamin B12 and folate deficiency: should we use a different cutoff value for hematologic disorders?

Anemia and macrocytosis are well-defined expected hematologic findings of vitamin B12 and folate deficiency; however, some previous studies did not show a significant association of subnormal B12 with anemia and macrocytosis. We retrospectively analyzed 17713 laboratory patient records to evaluate vitamin B12 and folate levels in relation to anemia and macrocytosis. In an age- and sex-adjusted logistic regression model, low B12 status but not marginal B12 status was significantly associated with anemia [ORs respectively, 1.291 (95% CI, 1.182-1.410), 1.022 (95% CI, 0.943-1.108)] and macrocytosis [ORs, respectively, 3.853 (95% CI, 3.121-4.756), 1.031 (95% CI, 0.770-1.381)]. Also low folate status but not marginal folate status was significantly associated with anemia [adjusted ORs, respectively, 1.819 (95% CI, 1.372-2.411), 1.101 (95% CI, 0.931-1.301)] and macrocytosis [adjusted ORs, respectively, 2.945 (95% CI, 1.747-4.965), 1.228 (95% CI, 0.795-1.898)]. Our results show that increased anemia and macrocytosis are observed at values below commonly used B12 lower-reference thresholds. Determining a hematologic cutoff value may help physicians in clinical practice.

Impact of folate supplementation on the efficacy of sulfadoxine/pyrimethamine in preventing malaria in pregnancy: the potential of 5-methyl-tetrahydrofolate

Malaria remains the leading cause of mortality and morbidity in children under the age of 5 years and pregnant women. To counterbalance the malaria burden in pregnancy, an intermittent preventive treatment strategy has been developed. This is based on the use of the antifolate sulfadoxine/pyrimethamine, taken at specified intervals during pregnancy, and reports show that this approach reduces the malaria burden in pregnancy. Pregnancy is also associated with the risk of neural tube defects (NTDs), especially in women with low folate status, and folic acid supplementation is recommended in pregnancy to lower the risk of NTDs. Thus, in malaria-endemic areas, pregnant women have to take both antifolate medication to prevent malaria and folic acid to lower the risk of NTDs. However, the concomitant use of folate and antifolate is associated with a decrease in antifolate efficacy, exposing pregnant women to malaria. Thus, there is genuine concern that this strategy may not be appropriate. We have reviewed work carried out on malaria folate metabolism and antifolate efficacy in the context of folate supplementation. This review shows that: (i) the folate supplementation effect on antifolate efficacy is dose-dependent, and folic acid doses required to protect pregnant women from NTDs will not decrease antifolate activity; and (ii) 5-methyl-tetrahydrofolate, the predominant form of folate in the blood circulation, could be administered (even at high dose) concomitantly with antifolate without affecting antifolate efficacy. Thus, strategies exist to protect pregnant women from malaria while maintaining adequate folate levels in the body to reduce the occurrence of NTDs.

Dietary Folate Intake and Blood Biomarkers Reveal High-Risk Groups in a Mediterranean Population of Healthy Women of Childbearing Potential

Background/Aims: An important public health issue is monitoring folate inadequacy in women of childbearing potential. The aim of the present study was to investigate associations between folate intake, red blood cell (RBC) folate, total homocysteine (tHcy) and the MTHFR 677T allele. Methods: A total of 204 women were enrolled in a cross-sectional study. Folate intake was assessed by a food frequency questionnaire, and RBC folate, tHcy and MTHFR C677T genotype were determined. Results: About half of the women had a decreased RBC folate level (<305 nmol/l) and all were <906 nmol/l, even though 51% of the subjects reported use of supplements. Overall 91.5% had a high Hcy concentration. Notably, younger women, and those with a low level of education, were shown to be at higher risk of inadequate RBC folate levels. Additionally, younger women were also at higher risk of carrying the TT genotype, particularly unfavorable in the setting of a low folate status. Conclusions: Our study revealed significant folate deficiency in our Mediterranean population and higher than ideal Hcy concentrations, thus emphasizing that in these groups an improvement in the folate status is needed via a food-based approach or supplement. Consequently, public health policy strategies aiming at improved supplementation are required.