Red Cell Folate Research Articles

Short interpregnancy intervals, maternal folate levels, and infants born small for gestational age: a preliminary study in a Canadian supplement-using population.

Short interpregnancy intervals (SIPI) have been associated with increased risks for adverse neonatal outcomes including preterm delivery and infants small for gestational age (SGA). It has been suggested that mechanistically, adverse neonatal outcomes after SIPI arise due to insufficient recovery of depleted maternal folate levels prior to the second pregnancy. However, empirical data are lacking regarding physiological folate levels in pregnant women with SIPI and relationships between quantified physiological folate levels and outcomes like SGA. Therefore, we sought to test 2 hypotheses, specifically that compared with controls women with SIPI would: (i) have lower red blood cell folate (RBCF) levels and (ii) be more likely to have SGA infants (defined as <10th percentile). Using data collected in British Columbia, Canada, for a larger study on perinatal psychopathology, we documented supplementation use and compared prenatal RBCF levels and proportion of SGA infants between women with SIPI (second child conceived ≤24 months after previous birth, n = 26) and matched controls (no previous pregnancies, or >24 months between pregnancies, n = 52). There were no significant differences in either mean RBCF levels (Welch's t test, p = 0.7) or proportion of SGA infants (Fisher's exact test, p = 0.7) between women with SIPI and matched controls. We report the first data about RBCF levels in the context of SIPI. If confirmed, our finding of no relationship between these variables in this population suggests that continued folic acid supplementation following an initial pregnancy mitigates folate depletion. We found no relationship between SIPI and SGA.

One-Carbon Metabolism Biomarkers and Cognitive Decline in the Very Old: The Newcastle 85+ Study

ObjectivesAlthough the biological rationale for the association between folate, vitamin B12, and homocysteine with cognitive function seems plausible, conflicting results have been reported. This study aimed to determine the associations between 1-carbon (1-C) metabolism biomarkers (folate, vitamin B12, and homocysteine), and cognitive impairment at baseline and the rate of cognitive decline over 5 years in the very old. DesignThe Newcastle 85+ Study was a prospective longitudinal study of people 85 years old and followed over 5 years in Northeast England. SettingCommunity-dwelling and institutionalized. ParticipantsThe analytical sample included 765 very old participants with 1-C metabolism biomarkers and cognitive measures. MeasurementsGlobal cognition was measured by the Standardized Mini-Mental State Examination (SMMSE) at baseline, and at 3 and 5 years of follow-up and, attention-specific cognition with the Cognitive Drug Research (CDR) System at baseline, and at 1.5 and 3.0 years of follow-up. Baseline red blood cell folate (RBC folate), plasma vitamin B12, and total homocysteine (tHcy) concentrations were determined by immunoassay. Linear mixed models were used to estimate the associations between quartiles of 1-C metabolism biomarkers and cognition over 3 (CDR) and 5 years (SMMSE). ResultsCompared with participants in the lowest quartile of RBC folate concentrations (<612 nmol/L), those in the highest quartile of RBC folate concentrations (>1280 nmol/L) had 1 more point on the SMMSE at baseline (β = +1.02, SE = 0.43, P = .02). Those in quartile 4 of tHcy (>21.4 μmol/L) had 1 point less in the SMMSE at baseline than those in the lowest quartile (<13.5 μmol/L) (β = −1.05, SE = 0.46, P = .02). Plasma vitamin B12 was not predictive of global or attention-specific cognition at baseline and at follow-up. None of the 1-C metabolism biomarkers except tHcy was associated with the rate of decline in attention scores over 3 years. ConclusionRBC folate and tHcy, but not plasma vitamin B12, were associated with better global cognition in the very old at baseline but were not predictive of rate of decline over 5 years.

A Black Cohosh Extract Causes Hematologic and Biochemical Changes Consistent with a Functional Cobalamin Deficiency in Female B6C3F1/N Mice.

Black cohosh rhizome, available as a dietary supplement, is most commonly marketed as a remedy for dysmenorrhea and menopausal symptoms. A previous subchronic toxicity study of black cohosh dried ethanolic extract (BCE) in female mice revealed a dose-dependent ineffective erythropoiesis with a macrocytosis consistent with the condition known as megaloblastic anemia. The purpose of this study was to investigate potential mechanisms by which BCE induces these particular hematological changes. B6C3F1/N female mice (32/group) were exposed by gavage to vehicle or 1,000 mg/kg BCE for 92 days. Blood samples were analyzed for hematology, renal and hepatic clinical chemistry, serum folate and cobalamin, red blood cell (RBC) folate, and plasma homocysteine and methylmalonic acid (MMA). Folate levels were measured in liver and kidney. Hematological changes included decreased RBC count; increased mean corpuscular volume; and decreased reticulocyte, white blood cell, neutrophil, and lymphocyte counts. Blood smear evaluation revealed increased Howell-Jolly bodies and occasional basophilic stippling in treated animals. Plasma homocysteine and MMA concentrations were increased in treated animals. Under the conditions of our study, BCE administration caused hematological and clinical chemistry changes consistent with a functional cobalamin, and possibly folate, deficiency. Further studies are needed to elucidate the mechanism by which BCE causes increases in homocysteine and MMA.

Development of a Healthy Dietary Habits Index for New Zealand Adults.

Healthful dietary habits are individually associated with better nutrient intake and positive health outcomes; however, this information is rarely examined together to validate an indicator of diet quality. This study developed a 15-item Healthy Dietary Habits Index (HDHI) based on self-reported dietary habits information collected in the 2008/09 New Zealand Adult Nutrition Survey. The validity of HDHI as a diet quality index was examined in relation to sociodemographic factors, 24-diet recall derived nutrient intakes, and nutritional biomarkers in a representative sample of adults aged 19 years and above. Linear regression models were employed to determine associations between HDHI quintiles and energy-adjusted nutrient data and nutritional biomarkers. Significantly higher HDHI scores were found among women, older age groups, Non-Māori or Pacific ethnic groups, and less socioeconomically-deprived groups (all p < 0.001). Increasing quintiles of HDHI were associated with higher intakes of dietary fibre and seven micronutrients including calcium, iron, and vitamin C, and lower intakes of energy, macronutrients, sodium, zinc, vitamins B6 and B12. Associations in the expected directions were also found for urinary sodium, whole blood folate, serum and red blood cell folate, and plasma selenium (all p < 0.001). The present findings suggest that the HDHI is a valid measure of diet quality as it is capable of discerning quality of diets of subgroups and ranking nutrient intakes among NZ adults.

A Simplified Red Blood Cell Folate Calculation: Comparison to the Traditional Calculation Using Data from NHANES 2007–2010

Red blood cell folate (RBF) concentrationsare considered an accurate indicator of folate body stores and are usuallymeasured to assess the population baseline status or the impact of folateintervention. The traditional calculation of RBF requires 3 components, wholeblood folate (WBF), serum folate (SFOL), and hematocrit (Hct) and is calculatedas [WBF–SFOL(1–Hct/100)]/(Hct/100). In some cases data for SFOL and/or Hct maynot be available, but the hemoglobin (Hb) concentration is generally availablein health and nutrition surveys. Using data for persons 1 y and olderparticipating in NHANES 2007–2010 (n ~ 17000), we investigated whether asimplified calculation generated accurate RBF results. The available dataincluded SFOL and RBF measured by use of microbiologic assay, Hct, Hb, and meancell Hb content (MCHC); population median values for these indicators were 39.8nmol/L, 1070 nmol/L, 40.8%, 140 g/L, and 344 g/L, respectively. We calculatedthe WBF concentration as (RBF*Hct/100)+SFOL(1–Hct/100). We calculated anestimated Hct as Hb/MCHC, using the population median MCHC; the populationmedian estimated Hct was 40.8%. We investigated 5 simplified calculationscenarios: 1) use simple formula by ignoring SFOL (WBF/Hct); 2) use an imputed SFOLconcentration of 40 nmol/L; 3) use an imputed Hct value of 40%; 4) use an estimated Hct value; 5) use both an imputed SFOL value and an estimated Hct value with WBFand Hb being the only measured parameters. We compared geometric mean RBF results from these 5 scenarios with traditionally calculated RBF results for the entire population and demographic subgroups of age, gender and race‐ethnicity, as well as for women of reproductive age (WRA, 15–44 y). Compared to the traditional formula, the simple formula (ignoring SFOL) produced on average 5.6% (4.5–9.6% in subgroups; 5.9% in WRA) higher RBF results. Using an imputed SFOL concentration had on average 0% bias (−1.2% to 2.8% in subgroups; −1.2% in WRA). Using an imputed Hct value had on average 1.9% bias (−9.2% to 7.6% in subgroups; −3.9% in WRA). Using an estimatedHct had on average 0% bias (−3.5% to 3.5% in subgroups; 0% in WRA). Using both an imputed SFOL and an estimated Hct had on average 0% bias (−1.4% to 1.9%| in subgroups). In summary, ignoring the SFOL concentration in the calculation of RBF or using an imputed Hct value bias the RBF results by as much as 10% incertain demographic subgroups. Conversely, using the population median SFOL as an imputed value, or the estimated Hct, or a combination of the 2 parameters resulted in small average biases. This demonstrates the potential of simplifying the RBF calculation to estimate central tendency in a population by only measuring WBF and Hb in each study participant and by using an estimated population median SFOL value derived from a small subsample. However, this approach will not accurately predict an individual RBF value. These initial findings need to be confirmed in other data sets, particularly in settings with low folate status. Furthermore, the impact of the simplified calculation on prevalence estimates using different folate cutoff value has to be assessed.

Folic acid intake among U.S. women of childbearing age with suboptimal red blood cell folate concentrations for neural tube defect prevention

BackgroundA recent study reported that 22.8% of U.S. women of childbearing age have folate insufficiency, defined as red blood cell (RBC) folate below optimal concentrations needed for neural tube defect (NTD) prevention per guidelines established by the World Health Organization. Clinical trials have shown that consuming 400 μg of folic acid daily prevents NTDs.ObjectiveWe assessed the daily usual total folic acid intake and RBC folate status of women of childbearing age. We estimated the proportion of women consuming ≥400 μg folic acid/day, the daily amount recommended for NTD prevention for all women capable of becoming pregnant.MethodsWe used 2007–2012 data on non‐pregnant women aged 12–49 years (n = 4783) from the National Health and Nutrition Examination Survey (NHANES) and estimated daily usual total folic acid intake from all fortified foods and dietary supplements. Folate insufficiency was defined as an RBC folate concentration of &lt;748 nmol/L using the NHANES microbiologic assay, which is associated with prevalence of NTDs of ≥9 cases per 10,000 live births.ResultsAmong all women in our study, 21.2% (95% confidence interval [CI]: 18.0, 24.3) had an average total folic acid intake of ≥400 μg /day from fortified foods and supplements. The prevalence of folate insufficiency was 22.5% (95% CI: 20.3, 24.9). Among the subgroup of women with folate insufficiency (n = 1196), only 3.9% (95% CI: 2.0, 5.7) achieved the recommended daily intake of folic acid. Among all women in our study, median usual daily total folic acid intake was highest among non‐Hispanic Whites (264 μg) and lowest among non‐Hispanic Blacks (185 μg). However, among women with folate insufficiency, the median usual daily total folic acid intake did not differ by race/ethnicity. Among women with folate insufficiency, 69.7% (95%CI: 64.8, 74.1) had mandatorily fortified foods (i.e., enriched cereal grain products) as their only source of folic acid; 12.6% (95% CI: 9.7, 16.1) reported taking supplements containing folic acid in the previous 30 days. Among folate‐insufficient women who did not use supplements, less than 1% had usual total folic acid intake ≥400 μg/day.ConclusionsThe majority of U.S. women of childbearing age with RBC folate below the optimal concentration do not consume the amount of folic acid recommended for NTD prevention. Targeted programs and guidance might increase folic acid intake among groups of women at higher risks for folate insufficiency.Support or Funding InformationThis work was supported by the CDC.

Association of Added Sugars Intake with Physiologic Parameters in Adults: NHANES 2001–2012

The association of added sugars intake with liver enzymes, cardiovascular risk factors, and markers of red cell counts was determined using NHANES 2001–2012 data from adults (19+ years; n=26,402). Dietary intake was determined using 24‐hour dietary recall interviews using an Automated Multiple‐Pass Method. The usual intake of added sugars as a percent of energy was estimated using the Markov Chain Monte Carlo (MCMC) ratio method as implemented in v1.0 of the SAS programs published by the National Cancer Institute (NCI). Balanced repeated replication (BRR) was used for variance estimation. Subjects were separated into six groups: 0&lt;5, 5 to &lt;10, 10 to&lt;15, 15 to &lt;20, 20 to &lt;25, and ≥25% of energy as added sugars. Group trends and linear trends for were determined using linear regression (p&lt;0.01) for: alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, gamma‐glutamyl transferase, lactate dehydrogenase, blood pressure, high‐ and low‐density lipoprotein cholesterol, triglycerides, glucose, c‐reactive protein, waist circumference, ferritin, serum and red blood cell folate, hemoglobin, and hematocrit. None of the liver enzyme levels showed any significant association with added sugars intake. Mean plasma glucose levels (mg/dL) showed an inverse group (beta = −0.71; p=0.0003) and linear trend (beta = −0.13); p=0.0002) association with increasing percent energy of added sugars. No other cardiovascular risk factors, including metabolic syndrome, showed any association with added sugars intake. Only hemoglobin (g/dL) (beta = −0.03, p=0.0007; beta = 0.005, p=0.0013) and hematocrit (%) (beta = −0.09, p=0.0001; beta = −0.02, p=0.0002) showed a group or linear trend, respectively. No other statistical associations were found. These results suggest that the association of usual added sugars intake, as determined by sophisticated models, up to &gt;25% of energy, had limited effect on physiologic parameters in adults.Support or Funding InformationUSDA Hatch Project LAB 94209 and USDA/ARS through specific cooperative agreement 58‐6250‐6‐003 was received. Partial support was also received from the Corn Refiners Association.

Association of TCN2 rs1801198 c.776G>C polymorphism with markers of one-carbon metabolism and related diseases: a systematic review and meta-analysis of genetic association studies

Background: Vitamin B-12 (cobalamin) deficiency may produce severe neurologic and hematologic manifestations. Approximately 20-25% of circulating cobalamin binds to transcobalamin 2 (TCN2), which is referred to as active vitamin B-12. The G allele of the TCN2 c.776G>C (rs1801198) polymorphism has been associated with a lower plasma concentration of holotranscobalamin. However, genotype association studies on rs1801198 have led to conflicting results regarding its influence on one-carbon metabolism (OCM) markers or its association with pathologic conditions.Objective: We assessed the association of rs1801198 genotypes with OCM marker concentrations and primary risks of congenital abnormalities, cancer, and Alzheimer disease.Design: We conducted a systematic review of the literature that was published from January 1966 to February 2017 and included all studies that assessed the association between rs1801198 and OCM markers or a pathologic condition.Results: Thirty-four studies met the inclusion criteria. Subjects with the rs1801198 GG genotype had significantly lower concentrations of holotranscobalamin [standardized mean difference (SMD): -0.445 (95% CI: -0.673, -0.217; P < 0.001); I2 = 48.16% (95% CI: 0.00%, 78.10%; P = 0.07)] and higher concentrations of homocysteine (European descent only) [SMD: 0.070 (95% CI: 0.020, 0.120; P = 0.01); I2 = 0.00% (95% CI: 0.00%, 49.59%; P = 0.73)] than did subjects with the rs1801198 CC genotype. The meta-analysis on the association between rs1801198 and methylmalonic acid (MMA) lacked statistical power. No significant difference was observed regarding cobalamin, folate, and red blood cell folate. No significant association was observed between rs1801198 and primary risks of congenital abnormalities, cancer, or Alzheimer disease.Conclusions: Meta-analysis results indicate an influence of rs1801198 on holotranscobalamin and homocysteine concentrations in European-descent subjects. In addition, well-designed and -powered studies should be conducted for assessing the association between rs1801198 and MMA and clinical manifestations that are linked to a decreased availability of cobalamin. This review was registered at www.crd.york.ac.uk/prospero as CRD42017058504.

Folate and vitamin B12 concentrations are associated with plasma DHA and EPA fatty acids in European adolescents: the Healthy Lifestyle in Europe by Nutrition in Adolescence (HELENA) study.

This study aimed to examine the association between vitamin B6, folate and vitamin B12 biomarkers and plasma fatty acids in European adolescents. A subsample from the Healthy Lifestyle in Europe by Nutrition in Adolescence study with valid data on B-vitamins and fatty acid blood parameters, and all the other covariates used in the analyses such as BMI, Diet Quality Index, education of the mother and physical activity assessed by a questionnaire, was selected resulting in 674 cases (43 % males). B-vitamin biomarkers were measured by chromatography and immunoassay and fatty acids by enzymatic analyses. Linear mixed models elucidated the association between B-vitamins and fatty acid blood parameters (changes in fatty acid profiles according to change in 10 units of vitamin B biomarkers). DHA, EPA) and n-3 fatty acids showed positive associations with B-vitamin biomarkers, mainly with those corresponding to folate and vitamin B12. Contrarily, negative associations were found with n-6:n-3 ratio, trans-fatty acids and oleic:stearic ratio. With total homocysteine (tHcy), all the associations found with these parameters were opposite (for instance, an increase of 10 nmol/l in red blood cell folate or holotranscobalamin in females produces an increase of 15·85 µmol/l of EPA (P value <0·01), whereas an increase of 10 nmol/l of tHcy in males produces a decrease of 2·06 µmol/l of DHA (P value <0·05). Positive associations between B-vitamins and specific fatty acids might suggest underlying mechanisms between B-vitamins and CVD and it is worth the attention of public health policies.

Micronutrient Deficiency Following Esophagectomy for Cancer of the Upper Gastrointestinal Tract

Objectives: For those patients who achieve long-term survival following esophagectomy, altered digestion and malabsorption may lead to a range of adverse gastrointestinal sequelae, including micronutrient deficiencies. The aim of the current study was to determine the prevalence of specific micronutrient deficiencies in patients following esophagectomy. Methods: Levels of vitamin A, vitamin E, vitamin D, vitamin B1, vitamin B12, folate, ferritin, zinc and calcium were measured in a single non-fasting blood sample in patients who has undergone esophagectomy. Findings were compared to both patients who had undergone gastrectomy and an age matched Western control population. Results: Forty-Four patients (33 male, 65.5 ± 10.2 yrs) a median of 26 months (IQR 12-46) following either two or three stage esophagectomy were recruited. Deficiency in one or more micronutrients was observed in 64% of patients who underwent esophagectomy. Micronutrients most commonly deficient following esophagectomy were vitamin D (21%), vitamin B12 (32%), ferritin (16%) and zinc (25%). Compared to patients who underwent gastrectomy, levels of vitamin B12 and red cell folate were significantly lower, and levels of vitamin E were significantly higher in the blood of patients following esophagetomy. Compared to a Western control population the mean levels of vitamins A, E, D and B12, ferritin and zinc were lower in patients following esophagectomy. Conclusion: Micronutrient deficiency is common after esophagectomy affecting two thirds of all patients. Regular screening of vitamin D, vitamin B12, ferritin and Zinc levels should be considered as well as prophylactic supplementation in this patient group to prevent deficiency.

Hydroxytyrosol supplementation increases vitamin C levels in vivo. A human volunteer trial

Hydroxytyrosol (HT) is a main phenolic component of olive oil. In this study, we investigated the safety and effects produced by HT purified (99.5%) from olive mill waste. HT was administered at a daily dosage of 45mg for 8 weeks to volunteers with mild hyperlipidemia (n=14). We measured markers of cardiovascular disease risk, enzyme markers of several clinical conditions, hematology, antioxidant parameters, vitamins and minerals at baseline (T0), 4 weeks (T4) and 8 weeks (T8). The values obtained at T4 and T8 were compared with baseline. We found that the HT dose administered was safe and mostly did not influence markers of cardiovascular disease, blood lipids, inflammatory markers, liver or kidney functions and the electrolyte balance. Serum iron levels remained constant but a significant (P<0.05) decrease in ferritin at T4 and T8 was found. Serum folate and red blood cell folate levels were also reduced at T4 and T8. Finally, vitamin C increased by two-fold at T4 and T8 compared with levels at baseline. These results indicate a physiologically relevant antioxidant function for HT through increasing endogenous vitamin C levels.

Assessment of different folic acid supplementation doses for low-birth-weight infants.

The adequacy of 50 mcg folic acid supplementation given to low-birth-weight babies was investigated. The folate levels of the mothers and infants, and breastmilk, and the optimum dose for folic acid supplementation were also investigated. After obtaining blood from 141 low-birth-weight infants on the 1st day of life for serum and red cell folate levels, the infants were randomly allocated into three groups according to the folic acid supplement dose. Forty-six infants were given 25 μg/d folic acid, 39 were given 50 μg/d folic acid, and 44 were given 75 μg/d folic acid. Folic acid could not be given to 12 infants. Follow-up blood samples were obtained at the end of folic acid supplementation. Maternal samples for red cell and serum folate levels and breast milk folate levels were obtained within the first 48 hours and the samples for measuring breastmilk folate level were obtained on the 3rd day postnatally. The feeding modes of the infants, maternal folic acid intake, and details of neonate intensive care unit course were recorded. The mean birth weight and gestational age of the infants were found as 1788.2±478.4 g and 33.5±2.9 weeks, respectively. The mean serum and red cell folate levels on admission were found as 21.2±12.2 ng/mL and 922.7±460.7 ng/mL, respectively. The mean maternal serum and red cell folate levels and the mean breast milk folate levels were found as 12.3±7.5 ng/mL, 845.5±301.4 ng/mL, and 30.6±33.0 ng/m, respectively. The breast milk folate levels of mothers who were supplemented with folic acid during pregnancy were significantly higher compared with mothers who were not supplemented with folic acid (p<0.001). Infants who were supplemented with folic acid had higher follow-up serum folate levels compared with the basal level in all groups, but there was no statistically significant difference between the groups. This study showed that the folic acid doses of 25, 50, and 75 μcg/d affected serum folate levels similarly. We can conclude that the dose of 25 μcg/d is adequate for low-birth-weight infants.

Effect of Medications for Gastric Acid-Related Symptoms on Total Motile Sperm Count and Concentration: A Case-Control Study in Men of Subfertile Couples from the Netherlands.

IntroductionGastric acid-related symptoms are highly prevalent in the general population (21–40%), and more than 11% of individuals use medication for the treatment of these symptoms. The uptake of micronutrients is dependent on the gastrointestinal potential of hydrogen (pH).ObjectiveWe hypothesized that medication affecting gastrointestinal pH reduces the availability of B vitamins, thereby deranging one-carbon metabolism and detrimentally affecting spermatogenesis.MethodsThis explorative nested case–control study in men of subfertile couples investigated associations between medication used for gastric acid-related symptoms and semen parameters. We included 40 men using medication for gastric acid-related symptoms and 843 men not using medication. Semen analyses were performed between 70 days before and 21 days after the visit.ResultsThe use of medication was associated with a twofold higher risk of a low total motile sperm count [TMSC <1 × 106, odds ratio (OR) 2.090, p = 0.049] and negatively with sperm concentration (β −0.320, p = 0.028). Red blood cell folate was positively associated with TMSC (β 0.257, p = 0.026), sperm count (β 1.679, p = 0.013) and ejaculate volume (β 0.120, p = 0.023), and total homocysteine (tHcy) was negatively associated with sperm count (β −0.077, p = 0.021).ConclusionHere we delineate associations between the use of medication for gastric acid-related symptoms and poor semen quality in men of subfertile couples. The use of medication for gastric acid-related symptoms is associated with a twofold higher risk of a low TMSC and a decreased sperm concentration. Although these findings warrant further research on causality, the associations between folate, tHcy and semen quality emphasize the importance of preconception counselling in male subfertility.Electronic supplementary materialThe online version of this article (doi:10.1007/s40264-016-0488-8) contains supplementary material, which is available to authorized users.

Folate, homocysteine and selected vitamins and minerals status in infertile women

Objectives: Diet has been recognised as a crucial factor influencing fetal and maternal health. Adequate levels of substances such as homocysteine, folate and vitamin B12 have been associated with a higher rate of success in infertility treatments. Few data, however, are available on the average levels of micronutrients in the blood of reproductive-aged women, and specific values for adequate levels are not available. The aim of this cross-sectional study was to measure levels of folate, homocysteine and selected vitamins and minerals in women attending the infertility unit of an academic hospital for in vitro fertilisation (IVF).Methods: Fasting venous blood samples were taken in the morning during routine screening before IVF in order to measure: serum folate, red blood cell (RBC) folate, total plasma homocysteine, vitamin B12, vitamin A, vitamin E, serum iron and serum ferritin.Results: Among 269 women aged 37 ± 4 years, only 69% and 44% showed adequate levels of homocysteine and vitamin B12, respectively. Serum folate was appropriate in 78% of the study participants, but only a minority (12%) had a concentration of RBC folate regarded as optimal for the prevention of fetal neural tube defects. Serum levels of vitamin A, vitamin E, iron and ferritin were, however, appropriate in the vast majority of participants (>80%).Conclusion: Folate levels were largely inadequate among women attending an infertility clinic for IVF. Vitamin B12 levels were also found to be inadequate.

A thymidylate synthase polymorphism is associated with increased risk for bone toxicity among children treated for acute lymphoblastic leukemia.

Bone fractures and osteonecrosis frequently complicate therapy for childhood acute lymphoblastic leukemia (ALL). Bone toxicity has been associated with exposure to corticosteroids and methotrexate (MTX) and age greater than 10 years. We tested whether common genetic polymorphisms were associated with bone toxicity during treatment for ALL. A total of 615 of 794 children enrolled on Dana Farber Cancer Institute ALL Consortium protocol 05-001 (NCT00400946) met eligibility criteria for inclusion in this analysis. Nineteen candidate polymorphisms were selected a priori, targeting genes related to glucocorticoid metabolism, oxidative damage, and folate physiology. Polymorphisms were genotyped using either PCR-based allelic discrimination or PCR product length analysis. Twenty percent of subjects were homozygous for two 28 bp repeats (2R/2R, where 2R is two 28-nucleotide repeats within the 5' untranslated region [UTR] of the thymidylate synthase [TS] gene) within the 5' UTR of the gene for TS. This 2R/2R genotype was associated with increased risk of osteonecrosis among children younger than 10 years at diagnosis (multivariable hazard ratio [HR] 2.71; 95%confidence interval [CI] 1.23-5.95; P = 0.013), and with bone fracture among children ≥ 10 years (multivariable HR 2.10; 95%CI 1.11-3.96; P = 0.022). No significant association was observed between TS genotype and red blood cell (RBC) folate, RBC MTX, or relapse risk. A common genetic variant is associated with increased risk of osteonecrosis among children younger than 10 years at diagnosis and with bone fractures among older children. These findings suggest that children and adolescents with the 2R/2R TS genotype should be closely monitored for the development of bone toxicity during therapy for ALL, and support a clinical trial testing the efficacy of protective interventions specifically in this vulnerable population.

Applying inappropriate cutoffs leads to misinterpretation of folate status in the US population

Background: Folate cutoffs for risk of deficiency compared with possible deficiency were originally derived differently (experimental compared with epidemiologic data), and their interpretations are different. The matching of cutoffs derived from one assay with population-based data derived from another assay requires caution.Objective: We assessed the extent of folate-status misinterpretation with the use of inappropriate cutoffs.Design: In the cross-sectional NHANES, serum and red blood cell (RBC) folate were first measured with the use of a radioprotein-binding assay (RPBA) (1988–2006) and, afterwards, with the use of a microbiologic assay (2007–2010). We compared prevalence estimates for assay-matched cutoffs (e.g., with the use of an RPBA cutoff with RPBA data) and assay-mismatched cutoffs (e.g., with the use of microbiologic assay cutoff with RPBA data) for risk of deficiency on the basis of megaloblastic anemia as a hematologic indicator in persons ≥4 y of age (e.g., serum folate concentration <7 nmol/L and RBC folate concentration <305 nmol/L derived with the use of a microbiologic assay), possible deficiency on the basis of rising homocysteine as a metabolic indicator in persons ≥4 y of age (e.g., serum folate concentration <10 nmol/L and RBC folate concentration <340 nmol/L derived with the use of an RPBA), and insufficiency on the basis of elevated risk of neural tube defects in women 12–49 y old (e.g., RBC folate concentration <906 nmol/L derived with the use of a microbiologic assay).Results: Pre–folic acid fortification (1988–1994), risks of deficiency for assay-matched compared with assay-mismatched cutoffs were 5.6% compared with 16% (serum folate), respectively, and 7.4% compared with 28% (RBC folate), respectively; risks declined postfortification (1999–2006) to <1% compared with <1% (serum folate), respectively, and to <1% compared with 2.5% (RBC folate), respectively. Prefortification (1988–1994), risks of possible deficiency for assay-matched compared with assay-mismatched cutoffs were 35% compared with 56% (serum folate), respectively, and 37% compared with 84% (RBC folate), respectively; risks declined postfortification (1999–2006) to 1.9% compared with 7.0% (serum folate), respectively, and to 4.8% compared with 53% (RBC folate), respectively. Postfortification (2007–2010), risks of insufficiency were 3% (assay matched) compared with 39% (assay mismatched), respectively.Conclusions: The application of assay-mismatched cutoffs leads to a misinterpretation of folate status. This confusion likely applies to clinical assays because no comparability data are available, to our knowledge.

Dairy Intakes in Older Irish Adults and Effects on Vitamin Micronutrient Status: Data from the TUDA Study.

Consumption of dairy products has been associated with positive health outcomes including a lower risk of hypertension, improved bone health and a reduction in the risk of type 2 diabetes. The suggested dairy intake for health in older adults is three servings per day but recent analysis of the NHANES data for older adults reported 98% were not meeting these recommendations. No studies have investigated the consequences of such declines in the dairy intakes of Irish older adults and the subsequent effects on vitamin micronutrient status. To study the daily dairy intakes of older Irish adults and to examine how the frequency of dairy food consumption affects vitamin micronutrient status. Participants (n 4,317) were from the Trinity Ulster Department of Agriculture (TUDA) Study, a large study of older Irish adults (aged >60 yrs) designed to investigate gene-nutrient interactions in the development of chronic diseases of aging. The daily intake portion for milk, cheese and yoghurt was calculated from food frequency questionnaire (FFQ) responses. Blood samples were analysed for vitamin biomarkers as follows: vitamin B12 (total serum cobalamin and holotranscobalamin (holoTC)), folate (red cell folate (RCF) and serum folate), vitamin B2 (erythrocyte glutathione reductase activation coefficient (EGRac)), vitamin B6 (serum pyridoxal phosphate) and vitamin D (serum 25(OH)D). The mean total reported dairy intake was 1.16 (SD 0.79) portions per day with males consuming significantly fewer total dairy portions compared to females (1.07 vs 1.21 respectively) (P<0.05). There was no significant difference in total daily dairy serving intakes by age decade (60-69, 70-79, >80 yrs). Overall, only 3.5% of the total population (n 151) achieved the recommended daily dairy intake of three or more servings per day. A significantly higher proportion of females (4%) compared to males (2.4%) met these dairy requirements (P=0.011). Blood concentrations of vitamin B12 biomarkers, RCF, vitamin B2 and vitamin B6 were significantly worse in those with the lowest tertile of dairy intake (0-0.71 servings) compared to those in the highest tertile (1.50-4.50 servings) (P<0.05). This study found that more than 96% of the older adults sampled did not meet current daily dairy intake recommendations. The study is the largest to-date examining dairy intakes in older Irish adults, and provides evidence that daily dairy intakes (in particular yogurt) contribute significantly to the B-vitamin and vitamin D biomarker status of older adults. These results suggest that older adults who are already vulnerable to micronutrient inadequacies, are forgoing the nutritional advantages of vitamin-rich dairy products.

UV-associated decline in systemic folate: implications for human nutrigenetics, health, and evolutionary processes.

The purpose of this study was to examine whether UV exposure alters folate status according to C677T-MTHFR genotype, and to consider the relevance of this to human health and the evolutionary model of skin pigmentation. Total Ozone Mapping Spectrometer (TOMS) satellite data were used to examine surface UV-irradiance, as a marker of UV exposure, in a large (n = 649) Australian cross-sectional study population. PCR/RFLP analysis was used to genotype C677T-MTHFR. Overall, cumulative UV-irradiance (42 and 120 days pre-clinic) was significantly negatively related to red cell folate (RCF) levels. When the cohort was stratified by MTHFR-C677T genotype, the relationship between UV-irradiance (42 days pre-clinic) and RCF remained significant only in the cohorts containing carriers of the T allele. Statistically significant z-score statistics and interaction terms from genotype and UV-irradiance (p-interaction) demonstrated that genotype did modify the effect of UV-irradiance on RCF, with the largest effect of UV being demonstrated in the 677TT-MTHFR subjects. Data provide strong evidence that surface UV-irradiance reduces long-term systemic folate levels, and that this is influenced by the C677T-MTHFR gene variant. We speculate this effect may be due to 677TT-MTHFR individuals containing more 5,10CH2 -H4 PteGlu, and that this folate form may be particularly UV labile. Since UV-irradiance lowers RCF in an MTHFR genotype-specific way, there are likely implications for human health and the evolution of skin pigmentation.

Red blood cell folate vs serum folate: Which one to measure?

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Intakes of Folate and Vitamin B12 and Biomarkers of Status in the Very Old: The Newcastle 85+ Study.

Very old adults are at increased risk of folate and vitamin B12 deficiencies due to reduced food intake and gastrointestinal absorption. The main aim was to determine the association between folate and vitamin B12 intake from total diets and food groups, and status. Folate or vitamin B12 intakes (2 × 24 h multiple pass recalls) and red blood cell (RBC) folate or plasma vitamin B12 (chemiluminescence immunoassays) concentrations were available at baseline for 731 participants aged 85 from the Newcastle 85+ Study (North-East England). Generalized additive and binary logistic models estimated the associations between folate and vitamin B12 intakes from total diets and food groups, and RBC folate and plasma B12. Folate intake from total diets and cereal and cereal products was strongly associated with RBC folate (p < 0.001). Total vitamin B12 intake was weakly associated with plasma vitamin B12 (p = 0.054) but those with higher intakes from total diets or meat and meat products were less likely to have deficient status. Women homozygous for the FUT2 G allele had higher concentrations of plasma vitamin B12. Cereals and cereal products are a very important source of folate in the very old. Higher intakes of folate and vitamin B12 lower the risk of “inadequate” status.