Folate Abstracts 11

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Obesity is associated with increased red blood cell folate despite lower dietary intakes and serum concentrations.
(Bird et al., 2015) Download
BACKGROUND:  Folates are essential cofactors in metabolic pathways that facilitate biological methylation and nucleotide synthesis, and therefore have widespread effects on health and diseases. Although obesity is prevalent worldwide, few studies have investigated how obesity interacts with folate status. OBJECTIVE:  Based on data from the NHANES, this study aims to examine the association between body mass index (BMI) and obesity-related metabolic factors with blood folate status. METHODS:  A nationally representative sample of 3767 adults from the NHANES (2003-2006) was used as the study population. Regression analyses, with and without adjustment for demographic factors and dietary intakes, were performed to examine associations between BMI and metabolic factors with serum and RBC folate. RESULTS:  The results indicate serum folate concentrations were lower in obese groups compared to the desirable BMI and overweight categories, paralleling lower intakes in this group. In contrast, RBC folate increased incrementally with BMI. Regression analyses demonstrated an inverse relation between BMI and serum folate but a positive relation for RBC folate (P < 0.01). Waist circumference, serum triglycerides, and fasting plasma glucose each displayed significant positive relations with RBC folate (P < 0.01), although relations with serum folate were not significant and consistent. CONCLUSIONS:  In summary, obesity is associated with decreased serum folate, which parallels decreased folate intakes. In contrast, obesity is positively associated with RBC folate. Therefore, RBC folate, in addition to serum folate, should also be considered as a critical biomarker for folate status, especially in the obese population. Future research is needed to understand how obesity differentially alters serum and RBC folate status because they are associated with a variety of medical complications.


 

Unmetabolized folic acid prevalence is widespread in the older Irish population despite the lack of a mandatory fortification program
            (Boilson et al., 2012) Download
BACKGROUND: In 2006 the Food Safety Authority of Ireland recommended mandatory folic acid fortification of flour for the prevention of neural tube defects in addition to the existing extensive voluntary folic acid fortification culture in place there. This recommendation is now suspended until further scientific evidence surrounding safety becomes available. The safety issues include concerns about the masking of vitamin B-12 deficiency and potential cancer acceleration, both of which may be of concern for the elderly population. OBJECTIVE: The aim of this study was to measure the basal (fasted) concentrations of unmetabolized folic acid in the plasma of an elderly population group exposed to this liberal voluntary fortification of foodstuffs in Ireland. DESIGN: We invited participants aged 60-86 y from the Lifeways Cross-Generation Cohort Study to participate in this project. After providing informed consent, the participants were invited to provide fasting blood samples and to complete a standard food-frequency questionnaire and a questionnaire on recent and habitual intakes of folic acid. Samples were assayed for total plasma folate, red blood cell folate, homocysteine, and unmetabolized folic acid. RESULTS: A total of 137 subjects with a mean age of 67.4 y were studied. Unmetabolized folic acid was detected in 94.1% of the cohort with a mean concentration of 0.39 nmol/L (range: 0.07-1.59 nmol/L), accounting for 1.3% of total plasma folate. CONCLUSION: These results indicate unmetabolized folic acid in plasma in most of this elderly Irish cohort, even after an overnight fast. These results should be considered carefully by those legislating in this area.

Systematic review of adverse health outcomes associated with high serum or red blood cell folate concentrations.
            (Colapinto et al., 2016) Download
BACKGROUND:  To examine the relationship between reported high serum or red blood cell (RBC) folate status and adverse health outcomes. METHODS:  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. RESULTS:  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. CONCLUSIONS:  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.

Increased breast cancer risk at high plasma folate concentrations among women with the MTHFR 677T allele
            (Ericson et al., 2009) Download
BACKGROUND: Folate is involved in DNA synthesis and methylation and may thereby influence carcinogenesis. OBJECTIVES: We examined plasma folate (P-folate) concentration in relation to genotypes of the folate-metabolizing enzyme methylenetetrahydrofolate reductase [MTHFR 677C-->T (rs1801133) and 1298A-->C (rs1801131)]. We also explored whether P-folate was associated with risk of postmenopausal breast cancer overall and in subgroups with genetic variants of the MTHFR single nucleotide polymorphisms (SNPs). DESIGN: This nested case-control study included 313 cases (age 55-73 y at baseline) with invasive breast cancer and 626 control subjects, matched on age and blood-sample date, from the population-based Malmo Diet and Cancer cohort. P-folate and MTHFR genotypes were determined for 310 cases and 611 controls. P-folate according to genotype was calculated by using analysis of variance. Odds ratios were obtained by using logistic regression. All tests were 2-sided. RESULTS: The variant 677T allele was associated with lower P-folate. In women with the 677T allele, a high P-folate concentration was associated with increased breast cancer risk (P for trend across P-folate tertiles = 0.03). Interaction was seen between the 677C-->T SNP and P-folate (P = 0.002). A positive association, which was seen between P-folate and breast cancer risk in 1298AA women (P = 0.01), was probably due to linkage between the 2 SNPs. Overall, and in women with other genotypes, no significant associations were observed. CONCLUSIONS: Our results suggest an association of high P-folate concentration with increased risk of postmenopausal breast cancer in carriers of the 677T allele. The findings underline the importance of genetic variation of MTHFR in the complex relation between folate and cancer.


 

Metabolic evidence of vitamin B-12 deficiency, including high homocysteine and methylmalonic acid and low holotranscobalamin, is more pronounced in older adults with elevated plasma folate.
            (Miller et al., 2009) Download
BACKGROUND:  An analysis of data from the National Health and Nutrition Examination Survey indicated that in older adults exposed to folic acid fortification, the combination of low serum vitamin B-12 and elevated folate is associated with higher concentrations of homocysteine and methylmalonic acid and higher odds ratios for cognitive impairment and anemia than the combination of low vitamin B-12 and nonelevated folate. These findings await confirmation in other populations. OBJECTIVE:  The purpose was to compare metabolic indicators of vitamin B-12 status, cognitive function, and depressive symptoms among elderly Latinos with elevated and nonelevated plasma folate. DESIGN:  Cross-sectional data were analyzed for 1535 subjects (age: >or=60 y) from the Sacramento Area Latino Study on Aging. Subjects were divided into 4 groups on the basis of plasma vitamin B-12 (< or >or=148 pmol/L) and folate (<or= or >45.3 nmol/L). Homocysteine, methylmalonic acid, holotranscobalamin, ratio of holotranscobalamin to vitamin B-12, Modified Mini-Mental State Examination, delayed recall, and depressive symptom scores were compared between the groups. RESULTS:  Individuals with low vitamin B-12 and elevated folate (n = 22) had the highest concentrations of homocysteine and methylmalonic acid and the lowest concentration of holotranscobalamin and ratio of holotranscobalamin to vitamin B-12 when compared with all other groups (P <or= 0.003). No differences in Modified Mini-Mental State Examination, delayed recall, and depressive symptom scores were observed between the low vitamin B-12 and elevated-folate group compared with other groups. CONCLUSIONS:  Low vitamin B-12 is associated with more pronounced metabolic evidence of vitamin B-12 deficiency when folate is elevated than when folate is not elevated. These data should be considered when assessing the potential costs, risks, and benefits of folic acid and vitamin B-12 fortification programs.

Do high blood folate concentrations exacerbate metabolic abnormalities in people with low vitamin B-12 status
            (Mills et al., 2011) Download
BACKGROUND:  In elderly individuals with low serum vitamin B-12, those who have high serum folate have been reported to have greater abnormalities in the following biomarkers for vitamin B-12 deficiency: low hemoglobin and elevated total homocysteine (tHcy) and methylmalonic acid (MMA). This suggests that folate exacerbates vitamin B-12-related metabolic abnormalities. OBJECTIVE:  We determined whether high serum folate in individuals with low serum vitamin B-12 increases the deleterious effects of low vitamin B-12 on biomarkers of vitamin B-12 cellular function. DESIGN:  In this cross-sectional study, 2507 university students provided data on medical history and exposure to folic acid and vitamin B-12 supplements. Blood was collected to measure serum and red blood cell folate (RCF), hemoglobin, plasma tHcy, and MMA, holotranscobalamin, and ferritin in serum. RESULTS:  In subjects with low vitamin B-12 concentrations (<148 pmol/L), those who had high folate concentrations (>30 nmol/L; group 1) did not show greater abnormalities in vitamin B-12 cellular function in any area than did those with lower folate concentrations (≤30 nmol/L; group 2). Group 1 had significantly higher holotranscobalamin and RCF, significantly lower tHcy, and nonsignificantly lower (P = 0.057) MMA concentrations than did group 2. The groups did not differ significantly in hemoglobin or ferritin. Compared with group 2, group 1 had significantly higher mean intakes of folic acid and vitamin B-12 from supplements and fortified food. CONCLUSIONS:  In this young adult population, high folate concentrations did not exacerbate the biochemical abnormalities related to vitamin B-12 deficiency. These results provide reassurance that folic acid in fortified foods and supplements does not interfere with vitamin B-12 metabolism at the cellular level in a healthy population.

High serum folates and the simplification of red cell folate analysis.
            (Philpott et al., 2001) Download
Recent substantial increases in clinical blood folate concentrations are noted. Since red cell folates (RCF) are calculated from whole blood folates (WBF) by subtraction of the endogenous serum folate (SF) component, the reporting of clinical RCF results may be delayed because an ever increasing proportion (15%) of diagnostic SF levels are high (> 20 ng/ml) and need a repeat analysis. We evaluated 'plasma replacement' as a simple preanalytical procedure in which endogenous blood plasma is removed from red cells by washing and substituted with 'low-folate' plasma (serum) as an alternative conjugase (gamma-glutamyl carboxypeptidase) source for folate polyglutamate hydrolysis. Washed and conventional RCF assays compared well after both manual (n = 115, r = 0.98, y = 1x + 1.26) and automated washing of red cells (n = 170, r = 0.96, y = 0.96x - 0.73 ng/ml) and were not significantly different. The interassay reproducibility of folate results from washed blood samples was good (CV = < 6%). This novel 'plasma replacement' step halves the cost of a valid RCF assay by eliminating the need for endogenous SF analysis, and it expedites the reporting of clinical results.

High concentrations of folate and unmetabolized folic acid in a cohort of pregnant Canadian women and umbilical cord blood.
            (Plumptre et al., 2015) Download
BACKGROUND:  Mandatory fortification, prevalent supplement use, and public health guidelines recommending periconceptional supplementation have increased folic acid intakes in North American pregnant women. However, the effects of increased folic acid intakes during pregnancy on maternal and cord blood folate concentrations have not been well established. OBJECTIVES:  In this prospective study, we determined maternal and cord blood concentrations of folate and unmetabolized folic acid (UMFA) in a cohort of pregnant Canadian women and their newborns and examined the effect of maternal intakes of folate and folic acid and fetal genetic variants in folate metabolism on folate status. DESIGN:  Folate and folic acid intakes of 368 Canadian pregnant women were assessed in early (0-16 wk) and late (23-37 wk) pregnancy. Blood concentrations of folate and UMFA were measured with the use of immunoassays and liquid chromatography-mass spectrometry, respectively, in maternal samples in early pregnancy (12-16 wk), at delivery (28-42 wk), and in cord blood. Four fetal genetic variants of the 5,10-methylenetetrahydrofolate reductase (MTHFR) and dihydrofolate reductase (DHFR) genes were assessed for their association with cord blood concentrations of folate and UMFA. RESULTS:  Geometric mean (95% CI) maternal red blood cell (RBC) folate concentrations were 2417 nmol/L (2362, 2472 nmol/L ) and 2793 nmol/L (2721, 2867 nmol/L ) in early pregnancy and at delivery, respectively. The mean (95% CI) cord RBC folate concentration was 2689 nmol/L (2614, 2765 nmol/L). UMFA was detectable in >90% of maternal and cord plasma samples. Although 3 fetal MTHFR and DHFR genetic variants had no effect, the fetal MTHFR 677TT genotype was associated with significantly lower cord serum (P = 0.03) and higher cord RBC (P = 0.02) folate concentrations than those of the wild type. CONCLUSIONS:  Notwithstanding differences in assays, maternal and cord RBC folate and plasma UMFA concentrations were higher than previously reported values. Functional ramifications of high folate and UMFA concentrations in maternal and fetal circulation warrant additional investigation because an excess folate status may affect long-term health outcomes of the offspring. This study was registered at www.clinicaltrials.gov as NCT02244684.

In vitamin B12 deficiency, higher serum folate is associated with increased total homocysteine and methylmalonic acid concentrations.
            (Selhub et al., 2007) Download
In a recent study of older participants (age >/=60 years) in the 1999-2002 National Health and Nutrition Examination Survey (NHANES), we showed that a combination of high serum folate and low vitamin B(12) status was associated with higher prevalence of cognitive impairment and anemia than other combinations of vitamin B(12) and folate status. In the present study, we sought to determine the joint influence of serum folate and vitamin B(12) concentrations on two functional indicators of vitamin B(12) status, total homocysteine (tHcy) and methylmalonic acid (MMA), among adult participants in phase 2 of the NHANES III (1991-1994) and the NHANES 1999-2002. Exclusion of subjects who were <20 years old, were pregnant, had evidence of kidney or liver dysfunction, or reported a history of alcohol abuse or recent anemia therapy left 4,940 NHANES III participants and 5,473 NHANES 1999-2002 participants for the study. Multivariate analyses controlled for demographic factors, smoking, alcohol use, body mass index, self-reported diabetes diagnosis, and serum concentrations of creatinine and alanine aminotransferase revealed significant interactions between serum folate and serum vitamin B(12) in relation to circulating concentrations of both metabolites. In subjects with serum vitamin B(12) >148 pmol/liter (L), concentrations of both metabolites decreased significantly as serum folate increased. In subjects with lower serum vitamin B(12), however, metabolite concentrations increased as serum folate increased starting at approximately 20 nmol/L. These results suggest a worsening of vitamin B(12)'s enzymatic functions as folate status increases in people who are vitamin B(12)-deficient.

 


References

Bird, JK, et al. (2015), ‘Obesity is associated with increased red blood cell folate despite lower dietary intakes and serum concentrations.’, J Nutr, 145 (1), 79-86. PubMed: 25527662
Boilson, A., et al. (2012), ‘Unmetabolized folic acid prevalence is widespread in the older Irish population despite the lack of a mandatory fortification program’, Am J Clin Nutr, PubMed: 22854405
Colapinto, CK, et al. (2016), ‘Systematic review of adverse health outcomes associated with high serum or red blood cell folate concentrations.’, J Public Health (Oxf), 38 (2), e84-97. PubMed: 26160024
Ericson, U. C., et al. (2009), ‘Increased breast cancer risk at high plasma folate concentrations among women with the MTHFR 677T allele’, Am J Clin Nutr, 90 (5), 1380-89. PubMed: 19759169
Miller, JW, et al. (2009), ‘Metabolic evidence of vitamin B-12 deficiency, including high homocysteine and methylmalonic acid and low holotranscobalamin, is more pronounced in older adults with elevated plasma folate.’, Am J Clin Nutr, 90 (6), 1586-92. PubMed: 19726595
Mills, JL, et al. (2011), ‘Do high blood folate concentrations exacerbate metabolic abnormalities in people with low vitamin B-12 status’, Am J Clin Nutr, 94 (2), 495-500. PubMed: 21653798
Philpott, N, et al. (2001), ‘High serum folates and the simplification of red cell folate analysis.’, Clin Lab Haematol, 23 (1), 15-20. PubMed: 11422225
Plumptre, L, et al. (2015), ‘High concentrations of folate and unmetabolized folic acid in a cohort of pregnant Canadian women and umbilical cord blood.’, Am J Clin Nutr, 102 (4), 848-57. PubMed: 26269367
Selhub, J, MS Morris, and PF Jacques (2007), ‘In vitamin B12 deficiency, higher serum folate is associated with increased total homocysteine and methylmalonic acid concentrations.’, Proc Natl Acad Sci U S A, 104 (50), 19995-20000. PubMed: 18056804