Dataset Information

Circulating unmetabolized folic acid and 5-methyltetrahydrofolate and risk of breast cancer: a nested case-control study.

ABSTRACT:

Background/objectives

Folates found in natural foods are thought to protect against cancer. However, folic acid (FA), a synthetic form of folate used in supplements and fortified foods, may increase breast cancer risk if present in unmetabolized form (UMFA) in the circulation. This study examined the associations of serum UMFA and 5-methyltetrahydrofolate (5-mTHF), the predominant form of circulating folate, with breast cancer risk.

Subjects/methods

We conducted a nested case-control study in a prospective cohort. In total, 553 cases of invasive breast cancer, diagnosed before mandatory FA fortification of grain in the US in 1998, were individually-matched to 1059 controls. Serum UMFA and 5-mTHF were measured using liquid chromatography-tandem mass spectrometry in stored serum samples, and 5-mTHF was corrected for storage degradation.

Results

Serum UMFA was not associated with breast cancer risk: the percentage of women with detectable levels of UMFA was similar in cases and controls (18% and 20%, respectively; p?=?0.46). Two tag-SNPs in the promoter region of the FA-metabolizing gene were also not associated with risk. There was a marginally significant inverse association of 5-mTHF_corrected with breast cancer risk (odds ratio for the highest vs. lowest quintile?=?0.69, 95% CI?=?0.49 to 0.97; p_trend?=?0.08).

Conclusions

Circulating UMFA was not associated with breast cancer risk. These results apply to countries without mandatory FA food fortification. Studies are needed in countries with mandatory fortification, where levels of UMFA are much higher than in our study.

SUBMITTER: Koenig KL

PROVIDER: S-EPMC7508257 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Publications

Circulating unmetabolized folic acid and 5-methyltetrahydrofolate and risk of breast cancer: a nested case-control study.

Koenig Karen L KL Scarmo Stephanie S Afanasyeva Yelena Y Clendenen Tess V TV Ueland Per Magne PM Zeleniuch-Jacquotte Anne A

European journal of clinical nutrition 20200421 9

<h4>Background/objectives</h4>Folates found in natural foods are thought to protect against cancer. However, folic acid (FA), a synthetic form of folate used in supplements and fortified foods, may increase breast cancer risk if present in unmetabolized form (UMFA) in the circulation. This study examined the associations of serum UMFA and 5-methyltetrahydrofolate (5-mTHF), the predominant form of circulating folate, with breast cancer risk.<h4>Subjects/methods</h4>We conducted a nested case-cont ...[more]

PMID: 32317749

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Project description:BackgroundThere is growing concern regarding elevated levels of circulating unmetabolized folic acid (UMFA) due to excessive intake of folic acid (FA). However, no randomized clinical trial has been conducted to examine the FA-UMFA dose-response relationship.ObjectiveThis study aimed to investigate the FA-UMFA dose-response relationship in Chinese adults with hypertension and elevated homocysteine (H-type hypertension), a population with clear clinical indication for FA treatment.MethodsThe data for this study were derived from a randomized, double-blind, multicenter clinical trial of 8 FA dosages on efficacy of homocysteine (Hcy) lowering. The parent trial had three 3 stages: screening period (2-10 days), run-in period (0-2 weeks, baseline visit), and double-blind treatment period (8 weeks) with follow-up visits at the end of the 2nd, 4th, 6th, and 8th weeks of treatment. Participants were randomly assigned to 8 treatment groups corresponding to FA dosages of 0, 0.4, 0.6, 0.8, 1.2, 1.6, 2.0 mg to 2.4 mg.ResultsThis study included 1,567 Chinese adults aged ≥45 years with H-type hypertension. There was a positive but non-linear association between FA supplementation and UMFA levels in the dosage range of 0 mg to 2.4 mg. In the regression analysis, the coefficients for the linear and quadratic terms of FA dosage were both statistically significant (P < 0.001). Notably, the slope for UMFA was greater for FA dosages >0.8 mg (ß = 11.21, 95% CI: 8.97, 13.45) compared to FA dosages ≤0.8 mg (ß = 2.94, 95% CI: 2.59, 3.29). Furthermore, FA dosages higher than 0.8 mg did not confer additional benefits in terms of increasing 5-methyl tetrahydrofolic acid (5-MTHF, active form of folate) or reducing homocysteine (Hcy).ConclusionIn Chinese adults with H-type hypertension, this study showed a positive, non-linear, dosage-response relationship between FA supplementation ranging from 0 to 2.4 mg and circulating UMFA levels. It revealed that 0.8 mg FA is an optimal dosage in terms of balancing efficacy (increasing 5-MTHF and lowering Hcy) while minimizing undesirable elevation of UMFA.Clinical trial registrationhttps://clinicaltrials.gov/ct2/show/NCT03472508?term=NCT03472508&draw=2&rank=1, identifier NCT03472508.

Project description:BackgroundMaternal nutrition and genetics are determinants of breast-milk nutrient composition and, as such, are determinants of the nutritional exposure of breastfed infants.ObjectivesThe aim of this study was to determine whether common maternal single nucleotide polymorphisms (SNPs) in folate-dependent enzymes are associated with breast-milk folate content in a cohort of mothers enrolled in the Maternal-Infant Research on Environmental Chemicals (MIREC) study.MethodsThe MIREC study is a Canadian prospective pregnancy cohort study that recruited 2001 participants between 2008 and 2011. Five folate-related SNPs-MTHFR 677C>T (rs1801133), MTHFR 1298A>C (rs1801131), MTHFR 1793G>A (rs2274976), MTR 2756A>G (rs1805087), and MTRR 66A>G (rs1801394)-were genotyped. Breast milk was sampled ∼1 mo postpartum, and tetrahydrofolate (THF), 5-methyl-THF, 5-formyl-THF, 5,10-methenyl-THF, and unmetabolized folic acid (UMFA) were measured using liquid chromatography-tandem mass spectrometry in a subset of participants (n = 551). Associations were assessed using Wald's test. Associations were considered significant if P ≤ 0.01 (Bonferroni correction for multiple testing).ResultsNone of the SNPs were associated with total breast-milk folate. However, the MTHFR 677C>T SNP was associated with breast-milk UMFA (R2 = 0.01; unadjusted P = 0.004), explaining a small portion of total variance; this association remained significant when adjusted for other covariates, including supplemental folic acid consumption. The MTHFR 1793G>A and MTRR 66A>G SNPs tended to be associated with 5-methyl-THF (R2 = 0.008, P = 0.04) and reduced folates (THF + 5-methyl-THF + 5-formyl-THF + 5,10-methenyl-THF; R2 = 0.01, P = 0.02), respectively.ConclusionsWe found that total breast-milk folate content was not associated with any of the folate-related SNPs examined. The association between the MTHFR 677C>T SNP and breast-milk UMFA, albeit modest, highlights the need to better understand the determinants of breast-milk folate and the impact they might have on milk folate bioavailability.

Dataset Information

Circulating unmetabolized folic acid and 5-methyltetrahydrofolate and risk of breast cancer: a nested case-control study.

Background/objectives

Subjects/methods

Results

Conclusions

Publications

Circulating unmetabolized folic acid and 5-methyltetrahydrofolate and risk of breast cancer: a nested case-control study.

Similar Datasets

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