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European Journal of Nutrition
Published in: European Journal of Nutrition 8/2019

01-12-2019 | Original Contribution

Presence of circulating folic acid in plasma and its relation with dietary intake, vitamin B complex concentrations and genetic variants

Authors: Josiane Steluti, Christina Reginaldo, Jacob Selhub, Ligi Paul, Regina Mara Fisberg, Dirce Maria Marchioni

Published in: European Journal of Nutrition | Issue 8/2019

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Abstract

Purpose

The aim of this study was to investigate circulating folic acid (FA) and predict circulating FA concentrations in the population related to dietary intake, vitamin concentrations, and interaction with the genetic variants involved in folate metabolism.

Methods

Data were from the ‘Health Survey of São Paulo’ a cross-sectional population-based survey, conducted in São Paulo City, Brazil. The participants (n = 750) provided fasting blood samples and food intake data. Folate, homocysteine, and B6 and B12 vitamins were assayed. DNA was isolated, and the genotypes for polymorphisms involved in folate metabolism were determined. A generalized linear model was performed to predict circulating FA concentration.

Results

The circulating FA was detected in 80.0% of the population, with a median concentration of 1.6 nmol/L (IQR 0.5–2.9). The increase of circulating FA concentrations was directly associated with total folate concentration (β coeff. 1.03; 95% CI 1.02–1.04), age (β coeff. 1.01; 95% CI 1.01–1.02), current smoker (β coeff. 1.51; 95% CI 1.16–1.97), self-reported skin color (β coeff. 1.83; 95% CI 1.51–2.20), as well as interaction between folate concentration and 19-bp deletion polymorphism in DHFR (β coeff. 1.02; 95% CI 1.01–1.03), and inversely associated with vitamin B6 (β coeff. 0.99; 95% CI 0.98–0.99).

Conclusions

In the current study, the presence of detectable circulating folic acid is high, and its concentration is elevated compared with other populations. Age, smoking, lower concentration of vitamin B6 and genetic variant are associated with increased levels of circulating FA. Further researches are needed to acknowledge and guarantee the safety of exposure to folic acid, especially in countries which have mandatory fortification.
Literature
1.
Blom HJ, Shaw GM, den Heijer M et al (2006) Neural tube defects and folate: case far from closed. Nat Rev Neurosci 7:724–731PubMedPubMedCentral
2.
Caudill MA (2010) Folate bioavailability: implications for establishing dietary recommendations and optimizing status. Am J Clin Nutr 91(Suppl 5):S1455–S1460
3.
FAO/WHO—Food and Agriculture Organization/World Health Organization (2001) Folate and Folic Acid. In: FAO/WHO expert consultation on human vitamin and mineral requirements. FAO, Rome
4.
Wright AJ, Dainty JR, Finglas PM (2007) Folic acid metabolism in human subjects revisited: potential implications for proposed mandatory folic acid fortification in the UK. Br J Nutr 98:667–675PubMed
5.
Hu J, Wang B, Sahyoun NR (2016) Application of the KeyEvents dose-response framework to folate metabolism. Crit Rev Food Sci Nutr 56:1325–1333PubMed
6.
Obeid R, Herrmann W (2012) The emerging role of unmetabolized folic acid in human diseases: myth or reality? Curr Drug Metab 13:1184–1195PubMed
7.
Hamner HC, Mulinare J, Cogswell ME et al (2009) Predicted contribution of folic acid fortification of corn masa flour to the usual folic acid intake for the US population: National Health and Nutrition Examination Survey 2001–2004. Am J Clin Nutr 89:305–315PubMed
8.
Quinlivan EP, Gregory JF 3rd (2003) Effect of food fortification on folic acid intake in the United States. Am J Clin Nutr 77:221–225PubMed
9.
Pfeiffer CM, Caudill SP, Gunter EW et al (2005) Biochemical indicators of B vitamin status in the US population after folic acid fortification: results from the National Health and Nutrition Examination Survey 1999–2000. Am J Clin Nutr 82:442–450PubMed
10.
Ganji V, Kafai MR (2006) Trends in serum folate, RBC folate, and circulating total homocysteine concentrations in the United States: analysis of data from National Health and Nutrition Examination Surveys, 1988–1994,1999–2000, and 2001–2002. J Nutr 136:153–158PubMed
11.
Kalmbach RD, Choumenkovitch SF, Troen AP et al (2008) A 19-base pair deletion polymorphism in dihydrofolate reductase is associated with increased unmetabolized folic acid in plasma and decreased red blood cell folate. J Nutr 138:2323–2327PubMedPubMedCentral
12.
Bailey RL, Mills JL, Yetley EA et al (2010) Unmetabolized serum folic acid and its relation to folic acid intake from diet and supplements in a nationally representative sample of adults aged> or = 60 y in the United States. Am J Clin Nutr 92:383–389PubMedPubMedCentral
13.
Kim YI (2007) Folic acid fortification and supplementation–good for some but not so good for others. Nutr Rev 65:504–511PubMed
14.
Mason JB (2011) Folate consumption and cancer risk: a confirmation and some reassurance, but we’re not out of the woods quite yet. Am J Clin Nutr 94:965PubMedPubMedCentral
15.
Sweeney MR, Staines A, Daly L et al (2009) Persistent circulating unmetabolised folic acid in a setting of liberal voluntary folic acid fortification. Implications for further mandatory fortification? BMC Public Health 9:295PubMedPubMedCentral
16.
17.
Marchioni DM, Verly E Jr, Steluti J et al (2013) [Folic acid intake before and after mandatory fortification: a population-based study in São Paulo, Brazil]. Cad Saude Publica 29:2083–2092PubMed
18.
de Carvalho AM, César CL, Fisberg RM et al (2014) Meat consumption in São Paulo-Brazil: trend in the last decade. PLoS One 9(5):e96667PubMedPubMedCentral
19.
Raper N, Perloff B, Ingwersen L et al (2004) An overview of USDA’s dietary intake data system. J Food Compost Anal 7:545–555
20.
Bagley PJ, Selhub J (2000) Analysis of folate from distribution by affinity followed by reversed-phase chromatography with electrical detection. Clin Chem 46:404 – 411PubMed
21.
Kalmbach R, Paul L, Selhub J (2011) Determination of unmetabolized folic acid in human plasma using affinity HPLC. Am J Clin Nutr 94:S343–S347
22.
Rybak ME, Jain RB, Pfeiffer CM (2005) Clinical vitamin B6 analysis: an interlaboratory comparison of pyridoxal 5′-phosphate measurements in serum. Clin Chem 51:1223–1231PubMed
23.
Beckman Coulter, Inc. (2009) Vitamin B12—Access Immunoassay Systems®. California (Technical Lab Manual)
24.
Abbott Diagnostics Division (2011) Homocysteine—Abbott Architect i2000. United Kingdom. (Technical Lab Manual)
25.
Miller S, Dykes D, Polesky H (1988) A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res 16:1215PubMedPubMedCentral
26.
Myakishev MV, Khripin Y, Hu S et al (2001) High-throughput SNP genotyping by allele-specific PCR with universal energy-transfer-labeled primers. Genome Res 11:163–169PubMedPubMedCentral
27.
Patanwala I, King MJ, Barrett DA et al (2014) Folic acid handling by the human gut: implications for food fortification and supplementation. Am J Clin Nutr 100:593–599PubMedPubMedCentral
28.
Kelly P, McPartlin J, Goggins M et al (1997) Unmetabolized folic acid in serum: acute studies in subjects consuming fortified food and supplements. Am J Clin Nutr 65:1790–1795PubMed
29.
Crider KS, Bailey LB, Berry RJ (2011) Folic acid food fortification-its history, effect, concerns, and future directions. Nutrients 3:370–384PubMedPubMedCentral
30.
Sweeney MR, McPartlin J, Scott J (2007) Folic acid fortification and public health: report on threshold doses above which unmetabolised folic acid appear in serum. BMC Public Health 7:41PubMedPubMedCentral
31.
Pfeiffer CM, Sternberg MR, Fazili Z et al (2015) Folate status and concentrations of serum folate forms in the US population: National Health and Nutrition Examination Survey 2011–2. Br J Nutr 113:1965–1977PubMedPubMedCentral
32.
Bailey SW, Ayling JE (2009) The extremely slow and variable activity of dihydrofolate reductase in human liver and its implications for high folic acid intake. Proc Natl Acad Sci USA 106:15424–15429PubMed
33.
Berry RJ, Bailey L, Mulinare J et al (2010) Fortification of flour with folic acid. Food Nutr Bull 31:S22–S35PubMed
34.
Fulgoni VL 3rd, Keast DR, Bailey RL et al (2011) Foods, fortificants, and supplements: where do Americans get their nutrients? J Nutr 141:1847–1854PubMedPubMedCentral
35.
Pfeiffer CM, Hughes JP, Lacher DA et al (2012) Estimation of trends in serum and RBC folate in the U.S. population from pre- to postfortification using assay-adjusted data from the NHANES 1988–2010. J Nutr 142:886–893PubMedPubMedCentral
36.
Kalmbach RD, Choumenkovitch SF, Troen AM et al (2008) Circulating folic acid in plasma: relation to folic acid fortification. Am J Clin Nutr 88:763–768PubMedPubMedCentral
37.
Pfeiffer CM, Sternberg MR, Fazili Z et al (2015) Unmetabolized folic acid is detected in nearly all serum samples from US children, adolescents, and adults. J Nutr 145:520–531PubMed
38.
39.
Sanderson P, McNulty H, Mastroiacovo P et al (2003) Folate bioavailability: UK Food Standards Agency workshop report. Br J Nutr 90:473–479PubMed
40.
Williams KT, Schalinske KL (2007) New insights into the regulation of methyl group and homocysteine metabolism. J Nutr 137:311–314PubMed
41.
Boen TR, Soeiro BT, Pereira-Filho ER et al (2008) Folic acid and iron evaluation in Brazilian enriched corn and wheat flours. J Braz Chem Soc 19:53–59
42.
Soeiro BT, Boen TR, Pereira-Filho ER et al (2010) Investigação da qualidade de farinhas enriquecidas utilizando Análise por Componentes Principais (PCA). Ciênc Tecnol Aliment 30:618–624
43.
Morris MS, Jacques PF, Rosenberg IH et al (2010) Circulating unmetabolized folic acid and 5-methyltetrahydrofolate in relation to anemia, macrocytosis, and cognitive test performance in American seniors. Am J Clin Nutr 91:1733–1744PubMed
44.
Choi SW, Mason JB (2000) Folate and carcinogenesis: an integrated scheme. J Nutr 30:129–132
45.
Giovannucci E (2002) Epidemiologic studies of folate and colorectal neoplasia: a review. J Nutr 132(Suppl 8):S2350–S2355
46.
Kim DH, Smith-Warner SA, Spiegelman D et al (2010) Pooled analyses of 13 prospective cohort studies on folate intake and colon cancer. Cancer Causes Control 21:1919–1930PubMedPubMedCentral
47.
Cole BF, Baron JA, Sandler RS et al (2007) Folic acid for the prevention of colorectal adenomas: a randomized clinical trial. JAMA 297:2351–2359PubMed
48.
Troen AM, Mitchell B, Sorensen B et al (2006) Unmetabolized folic acid in plasma is associated with reduced natural killer cell cytotoxicity among postmenopausal women. J Nutr 136:189–194PubMed
49.
Sawaengsri H, Wang J, Reginaldo C et al (2016) High folic acid intake reduces natural killer cell cytotoxicity in aged mice. J Nutr Biochem 30:102–107PubMed
50.
Hu J, Juan W, Sahyoun NR (2016) Intake and Biomarkers of Folate and Risk of Cancer Morbidity in Older Adults, NHANES 1999–2002 with Medicare Linkage. PLoS One 11:e0148697PubMedPubMedCentral
51.
Cho E, Zhang X, Townsend MK et al (2015) unmetabolized folic acid in prediagnostic plasma and the risk of colorectal cancer. J Natl Cancer Inst 107:djv260PubMedPubMedCentral
52.
Brunacio KH, Verly-Jr E, Cesar CL et al (2015) Use of dietary supplements among inhabitants of the city of São Paulo, Brazil. Cad Saude Publica 29:1467–1472
Metadata
Title
Presence of circulating folic acid in plasma and its relation with dietary intake, vitamin B complex concentrations and genetic variants
Authors
Josiane Steluti
Christina Reginaldo
Jacob Selhub
Ligi Paul
Regina Mara Fisberg
Dirce Maria Marchioni
Publication date
01-12-2019
Publisher
Springer Berlin Heidelberg
Published in
European Journal of Nutrition / Issue 8/2019
Print ISSN: 1436-6207
Electronic ISSN: 1436-6215
DOI
https://doi.org/10.1007/s00394-018-1852-5

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