Higher Serum Folate Research Articles

High Folate and Vitamin Low B12 Status: Potential Interactions with Cognitive Function Among U.S. Older Adults, NHANES 2011–2014

Abstract Objectives Potential safety concerns may exist with high folate/folic acid exposures combined with low vitamin B12 (B12) status relative to cognitive function; therefore, we investigated this relationship, leveraging cognitive test performance with folate and B12 biomarker data among a nationally-representative survey of U.S. older adults. Methods We analyzed data from 2420 older adults (≥60 y) from the 2011–2014 NHANES. High folate status was defined as unmetabolized serum folic acid (UMFA) > 1 nmol/L or serum folate > 74.1 nmol/L. Low B12 status was defined using age-specific cut-points for serum B12 [≤429 pmol/L (in 60–69 y) and ≤370 pmol/L (in ≥70 y)] or using a combination of traditional cut-points [elevated methylmalonic acid (>271 nmol/L) and deficient serum B12 (< 150 pmol/L)]. Multivariable logistic regression models estimated odds ratios (OR) of scoring low on one of four cognitive tests: Digit Symbol Substitution Test (DSST), Consortium to Establish a Registry for Alzheimer's Disease [CERAD; Word Learning (WL) and Delayed Recall (DR)], and Animal Fluency Test (AF). Results Among older adults with low B12 status, high UMFA was associated with a higher OR of having a low score on the DSST (<34, OR 2.16; 95% CI 1.05–4.47) and high serum folate was associated with a higher OR of having a low score on the AF (<14, OR 1.93; 95% CI 1.08–3.45), only when using traditional cut-points for B12. Among those with normal B12 status, having a high UMFA was protective on the CERAD-DR, regardless of B12 status being defined using age-specific or traditional cut-points. Compared to those with normal B12 (using traditional cut-points) and high UMFA, those with low B12 and high UMFA had a higher risk of scoring low on the DSST (<40, OR 2.22; 95% CI 1.31–3.75) and AF (<14, OR 1.97; 95% CI 1.30–2.97), those with low B12 and lower UMFA had a higher risk of scoring low on the DSST (<40, OR 1.69; 95% CI 1.16–2.47), and those with normal B12 and lower UMFA had a higher risk of scoring low on the CERAD-DR (<17, OR 1.38; 95% CI 1.02–1.85); similar patterns were found with serum folate. Conclusions In older adults, high folate was associated with better cognitive performance when vitamin B12 status is normal, whereas high folate was associated with poorer cognitive performance when vitamin B12 status is low. Funding Sources N/A.

Maternal blood folate status during early pregnancy and occurrence of autism spectrum disorder in offspring: a study of 62 serum biomarkers

BackgroundAutism spectrum disorder (ASD) evolves from an interplay between genetic and environmental factors during prenatal development. Since identifying maternal biomarkers associated with ASD risk in offspring during early pregnancy might result in new strategies for intervention, we investigated maternal metabolic biomarkers in relation to occurrence of ASD in offspring using both univariate logistic regression and multivariate network analysis.MethodsSerum samples from 100 women with an offspring diagnosed with ASD and 100 matched control women with typically developing offspring were collected at week 14 of pregnancy. Concentrations of 62 metabolic biomarkers were determined, including amino acids, vitamins (A, B, D, E, and K), and biomarkers related to folate (vitamin B9) metabolism, lifestyle factors, as well as C-reactive protein (CRP), the kynurenine-tryptophan ratio (KTR), and neopterin as markers of inflammation and immune activation.ResultsWe found weak evidence for a positive association between higher maternal serum concentrations of folate and increased occurrence of ASD (OR per 1 SD increase: 1.70, 95% CI 1.22–2.37, FDR adjusted P = 0.07). Multivariate network analysis confirmed expected internal biochemical relations between the biomarkers. Neither inflammation markers nor vitamin D3 levels, all hypothesized to be involved in ASD etiology, displayed associations with ASD occurrence in the offspring.ConclusionsOur findings suggest that high maternal serum folate status during early pregnancy may be associated with the occurrence of ASD in offspring. No inference about physiological mechanisms behind this observation can be made at the present time because blood folate levels may have complex relations with nutritional intake, the cellular folate status and status of other B-vitamins. Therefore, further investigations, which may clarify the potential role and mechanisms of maternal blood folate status in ASD risk and the interplay with other potential risk factors, in larger materials are warranted.

Serum Folate Levels in Patients with Chronic Hemolytic Anemia on Regular Folic Acid Supplementation Before and After Dose Modification

In light of the recommendation of folic acid supplementation in chronic hemolytic anemia, with possible supratherapeutic dosing and associated side effects, we performed this study to investigate serum folate levels in children with chronic hemolytic anemia. Phase 1 was a cross-sectional study of 134 patients in the Pediatric Hematology service, documenting daily dosage and performing serum folate levels. In phase 2, we reduced the dose to 1 mg for 148 patients and repeated the testing after six months. We found very high serum folate levels with Phase 1, with 93.2% above the upper level of normal. In Phase 2, values remained high with 42.5% above the acceptable upper limit. Doses of folic acid given to sickle cell and thalassemia patients exceed their actual needs. This should be re-evaluated to strike a balance between benefit and harm, with close monitoring of serum folate levels.

B-vitamins and body composition: integrating observational and experimental evidence from the B-PROOF study

PurposeHigher folate and vitamin-B12 have been linked to lower risk of overweight. However, whether this is a causal effect of these B-vitamins on obesity risk remains unclear and evidence in older individuals is scarce. This study aimed to assess the role of B-vitamin supplementation and levels on body composition in older individuals.MethodsA double-blind, randomized controlled trial in 2919 participants aged ≥ 65 years with elevated homocysteine levels. The intervention comprised a 2-year supplementation with a combination of folic acid (400 µg) and vitamin B12 (500 µg), or with placebo. Serum folate, vitamin-B12, active vitamin-B12 (HoloTC), methylmalonic acid (MMA), and anthropometrics were measured at baseline and after 2 years of follow-up. Dietary intake of folate and vitamin-B12 was measured at baseline in a subsample (n = 603) using a validated food-frequency questionnaire. Fat mass index (FMI) and fat-free mass index (FFMI) were assessed with Dual Energy X-ray absorptiometry (DXA).ResultsCross-sectional analyses showed that a 1 nmol/L higher serum folate was associated with a 0.021 kg/m2 lower BMI (95% CI − 0.039; − 0.004). Higher HoloTC (per pmol/L log-transformed) was associated with a 0.955 kg/m2 higher FMI (95% CI 0.262; 1.647), and higher MMA (per μgmol/L) was associated with a 1.108 kg/m2 lower FMI (95% CI − 1.899; − 0.316). However, random allocation of B-vitamins did not have a significant effect on changes in BMI, FMI or FFMI during 2 years of intervention.ConclusionsAlthough observational data suggested that folate and vitamin B12 status are associated with body composition, random allocation of a supplement with both B-vitamins combined versus placebo did not confirm an effect on BMI or body composition.

Serum folate and vitamin B12 status in young Brazilian children.

To assess the nutritional status of folate and vitamin B12 with anaemia in young children. A cross-sectional study was conducted at the primary health-care centres of four Brazilian cities. Folate and vitamin B12 were assessed by fluoroimmunoassay. Multilevel Poisson regression models were used to explore the association of folate and vitamin B12 status in relation to anaemia in young children. Brazil.ParticipantsChildren (n 460) aged 11 to 15 months. The median (interquartile range) of serum folate was 39·7 (28·8-55·3) nmol/l and only four children presented with folate deficiency (<10 nmol/l). Surprisingly, 30·9 % of children presented with serum folate concentrations above the upper limit of detectable values by the commercial kit used for analysis. The frequency of vitamin B12 deficiency (<148 pmol/l) was 15 % and it was inversely associated with the highest tertile of serum folate concentrations (P<0·001). Having high serum folate concentration (≥50·1 nmol/l) and vitamin B12≥148 pmol/l was associated with lower frequency of anaemia in these children (prevalence ratio=0·53; 95% CI 0·30, 0·92). High frequency of elevated serum concentration of folate was found among young Brazilian children and 15 % of them had vitamin B12 deficiency. The combination of high serum folate and normal vitamin B12 status was associated with a lower frequency of anaemia in these children. Improvements in the current strategies to promote healthy food-based complementary feeding along with prevention and control of micronutrient deficiencies are recommended to improve children's health.

Comparison of body condition score and other minimally invasive biomarkers between dogs with gastric carcinoma and dogs with chronic gastritis.

OBJECTIVE To identify minimally invasive biomarkers to help differentiate dogs with gastric carcinoma from those with chronic gastritis. DESIGN Prospective study. ANIMALS 15 dogs with gastric carcinoma, 29 dogs with chronic gastritis, and 7 healthy dogs. PROCEDURES Dogs with clinical signs of upper gastrointestinal tract disease for > 14 days that underwent gastroscopy or necropsy for collection of gastric biopsy specimens for histologic evaluation were prospectively enrolled. Gastric carcinoma and chronic gastritis were diagnosed on the basis of histologic findings. Additionally, gastric biopsy specimens were collected endoscopically from 7 healthy (control) dogs while they were anesthetized for a routine neutering procedure. Prior to being anesthetized for gastroscopy or euthanized, all dogs underwent a physical examination, and a blood sample was collected for quantification of select serum biomarker concentrations. Histologic findings, body condition score (BCS), and serum biomarker concentrations were compared among the 3 groups. RESULTS Dogs with gastric carcinoma were significantly older and had a significantly lower BCS, lower serum folate concentration, and greater serum C-reactive protein (CRP) concentration, compared with dogs with chronic gastritis and control dogs. CONCLUSIONS AND CLINICAL RELEVANCE Results suggested that age > 8 years, BCS < 4, serum CRP concentration > 25 mg/L, and an abnormally low serum folate concentration might be useful noninvasive biomarkers for identification of dogs with gastric carcinoma. For underweight older dogs with signs of upper gastrointestinal tract disease and high serum CRP and low serum folate concentrations, gastric biopsy specimens should be obtained and evaluated so that a prompt definitive diagnosis can be made and appropriate treatment initiated.

Serum cobalamin and folate as prognostic factors in canine exocrine pancreatic insufficiency: An observational cohort study of 299 dogs

Exocrine pancreatic insufficiency (EPI) in dogs is a gastrointestinal condition leading to a severe impairment of nutrient absorption. The disease is frequently associated with vitamin disturbances especially regarding cobalamin and folate. Dogs with EPI need daily expensive supportive treatment. The aim of the present study was to identify prognostic factors for EPI in dogs, through a long-term survival study of 299 dogs, taking into account epidemiological, clinical, biological and therapeutic data, with particular emphasis on serum cobalamin and folate concentration.The prevalence of low serum cobalamin (cobalamin<350ng/L) and high serum folate (folate>12μg/L) concentrations were 67% (200/299) and 55% (164/299), respectively. Dogs with hypocobalaminemia at diagnosis were significantly older than those with serum cobalamin concentration within the reference interval (P<0.001). Hypocobalaminemia at diagnosis (P=0.04), male sex (P=0.01), decreased appetite at diagnosis (P=0.008) and not receiving enzyme replacement therapy (P=0.003) were significant and independent risk factors for decreased survival in EPI. In contrast, hyperfolatemia was associated with improved prognosis (P=0.02). These results confirm the importance of measuring serum cobalamin and folate concentrations at the time EPI is diagnosed, as hypocobalaminemia is negatively associated with prognosis, particularly in the absence of a high serum folate concentration.

Harmonizing the Calibrator and Microorganism Used in the Folate Microbiological Assay Increases the Comparability of Serum and Whole-Blood Folate Results in a CDC Round-Robin Study

Harmonizing critical reagents for the folate microbiological assay (MBA) may improve among-laboratory comparability. We assessed the comparability of the MBA for serum folate (S-FOL) and whole-blood folate (WB-FOL) in an international comparison study. Eight laboratories obtained a kit containing CDC microorganism inoculum (chloramphenicol-resistant Lactobacillus rhamnosus), CDC calibrator (5-methyltetrahydrofolate), and 23 serum and WB hemolysate samples each. Laboratories analyzed the samples in single measurement over 2 d using 4 conditions: in-house microorganism and in-house calibrator (IH-MO & IH-CAL), in-house microorganism and CDC calibrator (IH-MO & CDC-CAL), CDC microorganism and in-house calibrator (CDC-MO & IH-CAL), and CDC microorganism and CDC calibrator (CDC-MO & CDC-CAL). We calculated geometric mean concentrations for each laboratory and condition and compared data to the CDC MBA (target). The among-laboratory arithmetic mean S-FOL concentrations for the 4 conditions were 30.2, 28.1, 30.0, and 29.9 (group 1, 5-methyltetrahydrofolate IH-CAL) compared with 35.3, 33.3, 33.6, and 30.7nmol/L (group 2, folic acid IH-CAL), respectively; and 428, 405, 398, and 393 (group 1) compared with 469, 423, 477, and 418nmol/L (group 2), respectively, for WB-FOL. Differences to the CDC MBA target values were smaller for group 1 (range across conditions; S-FOL: 9.9-21%; WB-FOL: 9.0-18%) compared with group 2 laboratories (S-FOL: 13-30%; WB-FOL: 16-32%) and smaller when CDC reagents were used compared with in-house reagents (S-FOL: 12% compared with 22%; WB-FOL: 13% compared with 25%). A linear mixed model estimated a small microorganism effect (S-FOL: 2.3%; WB-FOL: 2.3%) and a larger mean calibrator effect; folic acid compared with 5-methyltetrahydrofolate calibrator produced 12% higher S-FOL and 15% higher WB-FOL results. When laboratories used CDC reagents, the estimated among-laboratory variability was ∼10% for S-FOL and WB-FOL. Harmonizing the calibrator and microorganism for the folate MBA has the potential to improve the among-laboratory comparability in future surveys.

Cognitive impairment is associated with elevated serum homocysteine levels among older adults.

The aim of this study was to examine the associations between the risk of cognitive impairment and the serum levels of folate, vitamin B12, and homocysteine (Hcy). Subjects were persons aged 60-79years who participated in the Yangpyeong Cohort study between 2011 and 2012. Cognitive impairment and normal subjects consisted of 100 pairs of old adults matched by age, sex, and education levels. Cognitive function was evaluated with the Korean version of the Mini-Mental State Examination for Dementia Screening (MMSE-DS). Pearson's partial correlation coefficients and conditional multiple logistic regression analysis were applied to determine the associations between cognitive function and the serum levels of folate, vitamin B12, and Hcy. Compared with the matched normal group, the cognitive impairment group had higher proportions of folate deficiency (< 3ng/mL) and hyperhomocysteinemia (≥ 15µmol/L). Serum Hcy concentrations were inversely associated with serum folate (r = - 0.234, p = 0.001) and MMSE-DS score (r = - 0.150, p = 0.037) after adjusting for age, sex, and education. The high Hcy group showed a higher prevalence of cognitive impairment (4th vs. 1st quartile, OR 3.30, 95% CI 1.12-9.72, p for trend = 0.014) after adjusting for exercise. The present findings suggest a putative protective role of high serum folate and normal Hcy against cognitive impairment among older adults.

High Serum Folate Is Associated with Brain Atrophy in Older Diabetic People with Vitamin B12 Deficiency.

Previous studies have reported the adverse cognitive effects of high folate status in older individuals with vitamin B12 (VB12) deficiency. Thus, the aim of this study was to investigate how high serum folate and VB12 deficiency could collaboratively aggravate neuronal degeneration. In total, 146 older non-demented diabetic individuals with an average age of 75 ± 3.9 were recruited. VB12 deficiency and high folate status were based on high serum methylmalonic acid (MMA) concentrations (> 0.3 μmol/L) and the serum folate concentration being in the top tertile (> 31.4 nmol/L) respectively. Among these subjects, there were 20 with elevated MMA and high folate. The structural magnetic resonance imaging data of these subjects were analyzed by performing flexible factorial analysis with the "folate level" and "MMA level" added as main effects, and the interaction effect of folate and VB12 on brain volume was evaluated. The results showed significant gray matter atrophy of the right middle occipital gyrus and the opercular part of the inferior frontal gyrus in subjects with a simultaneous high folate status and VB12 deficiency. Together with previous observational studies on cognitive function, this study lends support to the notion that high serum folate concentrations in older people with VB12 deficiency may be associated with increased neurodegeneration.

High levels of circulating folate concentrations are associated with DNA methylation of tumor suppressor and repair genes p16, MLH1, and MGMT in elderly Chileans

BackgroundChanges in DNA methylation, one of the most studied epigenetic mechanisms, are considered an initial marker for early cancer detection. We evaluated how availability of dietary factors (folates and vitamin B12) involved in one-carbon metabolism may contribute to DNA methylation changes of cancer-related genes in human subjects.MethodsWe studied, by pyrosequencing, the methylation of tumor suppressor gene p16, DNA repair genes MLH1 and MGMT, and the repetitive element LINE-1 (as a surrogate for global DNA methylation), in blood of elderly individuals (n = 249) who had been exposed to folic acid (FA) through FA-fortified wheat flour during the last 12 years.ResultsWe found that serum folate and to a lesser extent, vitamin B12 concentrations, were significantly correlated with DNA methylation of p16, MLH1, and MGMT, but not with LINE-1. High serum folate concentrations (>45.3 nmol/L) were present in 31.1% of the participants. Although the methylated fraction of CpG sites in p16, MLH1, and MGMT was low (1.17–3.8%), high folate concentrations were significantly associated with methylation at the 3rd tertile of specific CpG sites in all genes with OR between 1.97 and 4.17.ConclusionsThis study shows that a public policy, like food fortification with FA that increases circulating serum folate levels, could affect methylation levels of specific genes linked to cancer risk. Our present results deserve additional studies to clarify the real impact of high FA levels for risk of cancer in a whole population chronically exposed to a fortified food such as wheat flour.Trial registrationISRCTN 48153354 and ISRCTN 02694183

Correspondence of folate dietary intake and biomarker data1–3

Background: Public health concerns with regard to both low and high folate status exist in the United States. Recent publications have questioned the utility of self-reported dietary intake data in research and monitoring.Objectives: The purpose of this analysis was to examine the relation between self-reported folate intakes and folate status biomarkers and to evaluate their usefulness for several types of applications.Design: We examined usual dietary intakes of folate by using the National Cancer Institute method to adjust two 24-h dietary recalls (including dietary supplements) for within-person variation and then compared these intakes with serum and red blood cell (RBC) folate among 4878 men and nonpregnant, nonlactating women aged ≥19 y in NHANES 2011-2012, a nationally representative, cross-sectional survey, with respect to consistency across prevalence estimates and rank order comparisons.Results: There was a very low prevalence (<1%) of folate deficiency when serum (<7 nmol/L) and RBC (<305 nmol/L) folate were considered, whereas a higher proportion of the population reported inadequate total dietary folate intakes (6%). Similar patterns of change occurred between intakes and biomarkers of folate status when distributions were examined (i.e., dose response), particularly when diet was expressed in μg. Intakes greater than the Tolerable Upper Intake Level greatly increased the odds of having high serum folate (OR: 17.6; 95% CI: 5.5, 56.0).Conclusions: When assessing folate status in the United States, where fortification and supplement use are common, similar patterns in the distributions of diet and biomarkers suggest that these 2 types of status indicators reflect the same underlying folate status; however, the higher prevalence estimates for inadequate intakes compared with biomarkers suggest, among other factors, a systematic underestimation bias in intake data. Caution is needed in the use of dietary folate data to estimate the prevalence of inadequacy among population groups. The use of dietary data for rank order comparisons or to estimate the potential for dietary excess is likely more reliable.

Vitamin B-12 treatment of asymptomatic, deficient, elderly Chileans improves conductivity in myelinated peripheral nerves, but high serum folate impairs vitamin B-12 status response assessed by the combined indicator of vitamin B-12 status

It is uncertain whether vitamin B-12 supplementation can improve neurophysiologic function in asymptomatic elderly with low vitamin B-12 status or whether folate status affects responses to vitamin B-12 supplementation. We assessed the effects of a single intramuscular injection of 10 mg vitamin B-12 (which also contained 100 mg vitamin B-6 and 100 mg vitamin B-1) on vitamin B-12 status and neurophysiologic function in elderly community-dwelling Chileans with low serum vitamin B-12 concentrations who were consuming bread fortified with folic acid. A pretreatment and posttreatment study was conducted in 51 participants (median ± SD age: 73 ± 3 y; women: 47%) with serum vitamin B-12 concentrations <120 pmol/L at screening. Vitamin B-12 status was defined by combining vitamin B-12, plasma total homocysteine (tHcy), methylmalonic acid (MMA), and holotranscobalamin into one variable [combined indicator of vitamin B-12 status (cB-12)]. The response to treatment was assessed by measuring cB-12 and neurophysiologic variables at baseline and 4 mo after treatment. Treatment increased serum vitamin B-12, holotranscobalamin, and cB-12 (P < 0.001) and reduced plasma tHcy and serum MMA (P < 0.001). Treatment produced consistent improvements in conduction in myelinated peripheral nerves; the sensory latency of both the left and right sural nerves improved on the basis of faster median conduction times of 3.1 and 3.0 ms and 3.3 and 3.4 ms, respectively (P < 0.0001). A total of 10 sensory potentials were newly observed in sural nerves after treatment. Participants with high serum folate at baseline (above the median, ≥33.9 nmol/L) had less improvement in cB-12 (P < 0.001) than did individuals whose serum folate was less than the median concentration (i.e., with a concentration <33.9 nmol/L). Asymptomatic Chilean elderly with poor vitamin B-12 status displayed improved conductivity in myelinated peripheral nerves after vitamin B-12 treatment and an interaction with folate status, which was detected only with the use of cB-12. This trial was registered at www.controlled-trials.com as ISRCTN02694183.

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

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

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

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

Race‐Ethnic Differences in B‐Vitamin Biomarkers and Intake Among US Adults in NHANES 2003–2006

The water‐soluble B‐vitamins folate, B‐6, and B‐12 are cofactors in 1‐carbon and amino acid metabolism. Low biomarker levels are associated with an increased risk for certain birth defects and/or chronic diseases. Serum folate (S‐FOL) and red blood cell folate (RBC‐FOL), serum pyridoxal‐5′‐phosphate (PLP) and pyridoxic acid (4PA), serum vitamin B‐12 (B‐12), and nutrient‐specific total vitamin intake (from diet based on one 24‐h recall and from supplements) were assessed as part of NHANES 2003–2006. We investigated race‐ethnic differences in these outcome variables in US adults (蠅20 y) stratified by nutrient‐specific supplement use. Spearman correlation coefficients between B‐vitamin biomarkers and total intake were mostly weak (r &lt;0.4); correlations were slightly higher in supplement users (SUP+; 0.23 蠄 r 蠄 0.46) compared to nonusers (SUP‐; 0.17 蠄 r 蠄 0.35). In SUP+, non‐Hispanic whites (NHW) had higher S‐FOL, RBC‐FOL, and 4PA, while non‐Hispanic blacks (NHB) had higher B‐12 geometric mean levels compared to NHW and Mexican Americans (MA). In SUP+, total median folate intake was higher in NHW compared to NHB, but there were no race‐ethnic differences for vitamins B‐6 and B‐12. In SUP‐, NHB had lower S‐FOL, RBC‐FOL, PLP, and 4PA geometric mean levels compared to MA and NHW; NHW had lower B‐12 concentrations compared to MA and NHB. In SUP‐, total median intakes for folate, B‐6, and B‐12 were lowest in NHB and similar in NHW and MA. These preliminary data show that race‐ethnic intake patterns in B‐vitamins do not always match biomarker patterns.

Helicobacter pylori seropositivity's association with markers of iron, 1-carbon metabolism, and antioxidant status among US adults: a structural equations modeling approach.

ObjectivesWe tested a model in which Helicobacter pylori seropositivity (Hps) predicted iron status, which in turn acted as a predictor for markers of 1-C metabolism that were then allowed to predict antioxidant status.MethodsNational Health and Nutrition Examination Surveys (NHANES 1999–2000) cross-sectional data among adults aged 20–85 y were analyzed (n = 3,055). Markers of Hps, iron status (serum ferritin and transferrin saturation (TS)); 1-C metabolism (serum folate (FOLserum), B-12, total homocysteine (tHcy), methylmalonic acid (MMA)) and antioxidant status (vitamins A and E) were entered into a structural equations model (SEM).ResultsPredictors of Hps included older age, lower education and income, racial/ethnic groups (lowest among Non-Hispanic Whites), and lifetime cigarette smoking. SEM modeling indicated that Hps had a direct inverse relationship with iron status (combining serum ferritin and TS) which in turn was positively related to 1-C metabolites (higher serum folate, B-12 or lower tHcy/MMA) that were positively associated with antioxidant status (combining serum vitamins A and E). Another pathway that was found bypassed 1-C metabolites (Hps → Iron_st → Antiox). The sum of all indirect effects from Hps combining both pathways and the other indirect pathways in the model (Hps → Iron_st → OneCarbon; Hps →OneCarbon →Antiox) was estimated at β = -0.006±0.003, p<0.05.ConclusionsIn sum, of the total effect of H. pylori seropositivity on antioxidant status, two significant indirect pathways through Iron status and 1-Carbon metabolites were found. Randomized controlled trials should be conducted to uncover the concomitant causal effect of H. pylori eradication on improving iron status, folate, B-12 and antioxidant status among H. pylori seropositive individuals.

The authors' reply.

We thank Dr. Kayadibi and colleagues (1) for their comments regarding our paper on hyperhomocysteinemia. (2) As it is known, vitamin B9, also called folate or folic acid, is one of the eighth forms of vitamin B. (3, 4) So, in the current study by Monfared et al. (2), folic acid is obviously considered as one of the forms of vitamin B, so the authors did not separately mention folic acid, and it is considered as an exclusion criteria. In addition, if despite adequate vitamin supplementation, adequately lowering plasma homocysteine has failed, the patients should be evaluated for vitamin deficiency, renal impairment, and thyroid dysfunction. It should be remembered that a (low) “normal” vitamin B12 level does not exclude intracellular vitamin B12 deficiency. Serum methylmalonic acid (MMA) and holotranscobalamin II levels are more reliable markers of vitamin B12 deficiency compared to the serum vitamin B12 concentration (5). Although Solomon demonstrated that high serum folate levels (>20 ng/mL) are associated with higher MMA, at the same time, homocysteine levels and cobalamin levels (201–300 pg/mL) are low normal. It should be mentioned that its effect is age dependent (≥60 years). In the case of having a normal range of serum folate, the effects would not progress (suggesting a threshold effect), but it would be reversed by cobalamin therapy (6). In our study, hyperhomocysteinemic patients had a mean folate level of 16.26±4.06 ng/mL (normal levels) with mid-normal cobalamin levels (405.56±169.28 pg/mL). It seems that, as Kayadibi et al. (1) proposed, evaluation of the functional deficiency of vitamin B12 by means of MMA, as an early functional marker of tissue vitamin B12 deficiency, could provide more accurate results. Further studies should consider this point. It is recommended by Kayadibi and colleagues (1) that multiple linear regression analysis should be performed with sex adjustment to eliminate tHcy differences that may be because of sex differences, so homogeneous distribution of sex would be achieved. As it is shown, in the univariate analysis, a significant association was found between tHcy and age (P=0.02), male sex (P=0001), serum creatinine (P=0.0001), blood urea nitrogen (P=0.0001), estimated creatinine clearance (P=0.001), the history of glomerulonephritis before transplantation (P=0.05), body mass index (P=0.02), serum uric acid (P=0.003), serum folate (P=0.0001), cyclosporine A dose (P=0.01), and CsA trough level (C0; P=0.02) (2). Then, in the multivariate analysis, multiple linear regression models were used by stepwise (entry=0.05, removal=0.1) method for determining associated factors of Hcy levels after adjusting all the demographic (including sex) and clinical variables (2). In response to tHcy analysis, fasting blood sample was collected into an ethylenediaminetetraacetic acid tube which was used for measuring plasma homocysteine of each patient. To separate the plasma, the blood sample was centrifuged immediately after collecting. Then the separated plasma was deeply frozen (−20°C). By this method, we tried to minimize the production and release of tHcy by red blood cells after obtaining the blood sample. (2) Congruent to the conclusion of Kayadibi and colleagues, we considered that measuring MMA, in addition to tHCY, folate, and vitamin B12, could reveal more accurate results. Ali Monfared 1 Seyyede Zeinab Azimi1 Ehsan Kazemnezhad1 Masoud Khosravi1 Mohammadkazem Lebadi1 Ebrahim Mirzajani2 Mohammad Najafi Ashtiani2 1 Urology Research Center School of Medicine Guilan University of Medical Sciences Rasht, Iran 2 School of Medicine Guilan University of Medical Sciences Rasht, Iran

Folate intake, serum folate levels, and prostate cancer risk: a meta-analysis of prospective studies.

BackgroundStudies have reported inconsistent results concerning the existence of associations of folate intake and serum folate levels with prostate cancer risk. This study sought to summarise the evidence regarding these relationships using a dose–response meta-analysis approach.MethodsIn January 2014, we performed electronic searches of PubMed, Embase, and the Cochrane Library to identify studies examining the effect of folate on the incidence of prostate cancer. Only prospective studies that reported effect estimates with 95% confidence intervals (CIs) of the incidence of prostate cancer for more than 2 categories of folate were included.ResultsOverall, we included 10 prospective studies reporting data on 202,517 individuals. High dietary folate intake had little or no effect on prostate cancer risk (risk ratio [RR] = 1.02; 95% CI = 0.95–1.09; P = 0.598). The dose–response meta-analysis suggested that a 100 μg per day increase in dietary folate intake has no significant effect on the risk of prostate cancer (RR = 1.01; 95% CI = 0.99–1.02; P = 0.433). However, high serum folate levels were associated with an increased risk of prostate cancer (RR = 1.21; 95% CI = 1.05–1.39; P = 0.008). The dose–response meta-analysis indicated that a 5 nmol/L increment of serum folate levels was also associated with an increased risk of prostate cancer (RR = 1.04; 95% CI = 1.00–1.07; P = 0.042).ConclusionsOur study indicated that dietary folate intake had little or no effect on prostate cancer risk. However, increased serum folate levels have potentially harmful effects on the risk of prostate cancer.Electronic supplementary materialThe online version of this article (doi:10.1186/1471-2458-14-1326) contains supplementary material, which is available to authorized users.

High serum folate might have a potential dual effect on risk of colorectal cancer

The possible dual role of serum folate in the development and progression of colorectal cancer (CRC) has not been well established in human studies. This study investigated the association between serum folate and the risk of CRC in subjects with CRC or colorectal adenomatous polyps (AP, a precursor of CRC), and healthy subjects. This study has a case-control design. Two hundred and thirty-seven men and 171 women were recruited with 156 subjects in the CRC group, 70 subjects in the AP group and 182 healthy subjects in the control group. The risk of CRC was significantly increased in the third (OR, 3.46; 95% CI, 1.16-10.34) and fourth (OR, 4.86; 95% CI, 1.42-16.58) quartiles of serum folate concentration after adjusting for potential confounders among subjects with AP or CRC. Furthermore, serum folate concentration had no significant effect on the risk of CRC among subjects in the control and CRC groups. Higher serum folate concentration was significantly correlated with increased CRC risk in subjects with AP, while serum folate had no effect on CRC risk in healthy controls. Serum folate might possess potential dual modulatory effects on the risk of CRC.