Vitamin C-related nutrient–nutrient and nutrient–gene interactions that modify folate status
Folate-related nutrient–nutrient and nutrient–gene interactions modify disease risk; we therefore examined synergistic relationships between dietary folic acid, vitamin C and variant folate genes with respect to red cell folate status.
Two hundred and twelve subjects were examined using chemiluminescent immunoassay, PCR and food frequency questionnaire to determine red cell and serum folate, 14 folate gene polymorphisms, dietary folate (natural and synthetic) and vitamin C.
When examined independently, synthetic PteGlu correlates best with red cell folate at higher levels of intake (p = 0.0102), while natural 5CH3-H4-PteGlun correlates best with red cell folate at lower levels of intake (p = 0.0035). However, dietary vitamin C and 5CH3-H4-PteGlun interact synergistically to correlate with red cell folate at higher levels of intake (p = 0.0005). No interaction between dietary vitamin C and PteGlu was observed. This ‘natural’ nutrient–nutrient interaction may provide an alternative to synthetic PteGlu supplementation that is now linked to adverse phenomena/health outcomes. On its own, vitamin C also correlates with red cell folate (p = 0.0150) and is strongly influenced by genetic variation in TS, MTHFR and MSR, genes critical for DNA and methionine biosynthesis that underpin erythropoiesis. Similarly, dietary vitamin C and 5CH3-H4-PteGlun act synergistically to modify red cell folate status according to variation in folate genes: of note, heterozygosity for 2R3R-TS (p = 0.0181), SHMT (p = 0.0046) and all three MTHFR SNPs (p = 0.0023, 0.0015 and 0.0239 for G1793A, C677T and A1298C variants, respectively) promote a significant association with red cell folate. Again, all these genes are critical for nucleic acid biosynthesis. Folate variants with the strongest independent effect on folate status were C677T-MTHFR (p = 0.0004) and G1793A-MTHFR (p = 0.0173).
5CH3-H4-PteGlun assimilation and variant folate gene expression products may be critically dependent on dietary vitamin C.
KeywordsAntioxidants Ascorbic acid Folic acid Polymorphism Vitamin Bioavailability
Conflict of interest
The authors declare that they have no conflict of interest.
- 1.Gregory JF III (2001) Case study: folate bioavailability. J Nutr 131:1376–1382Google Scholar
- 4.Sauberlich HE, Kretsch MJ, Skalah JH, Johnson HL, Talyor PC (1987) Folate requirement and metabolism in nonpregnant women. Am J Clin Nutr 46:1016–1028Google Scholar
- 5.Northwestern University (2004) http://www.feinberg.northwestern.edu/nutrition/factsheets/folate.pdf
- 6.Keagy PM (1985) Folacin: microbiological and animal assays. In: Methods of vitamin assay, 4th edn. Wiley, New York, pp 445–471Google Scholar
- 7.Blakeley RL (1969) The chemistry of folic acid and related pteridines. Front Biol 13:58–105Google Scholar
- 10.Scott JM (2001) Methyltetrahydrofolate: the superior alternative to folic acid. In: Nutraceuticals in health and disease prevention. Marcel Dekker, New York, pp 75–90Google Scholar
- 13.Giovannucci E (2004) Alcohol, one-carbon metabolism, and colorectal cancer: recent insights from molecular studies. J Nutr 134:2475S–2481SGoogle Scholar
- 14.Kim YI (2004) Folate and DNA methylation: a mechanistic link between folate deficiency and colorectal cancer? Cancer Epidemiol Biomarkers Prev 13:511–519Google Scholar
- 18.Smith DA, Kim YI, Refsum H (2008) Is folic acid good for everyone? Am J Clin Nutr 87:517–533Google Scholar
- 20.Lucock MD (1999) eBMJ; http://www.bmj.com/cgi/eletters/319/7202/92#EL1
- 26.Van der Put NMJ, Van der Molen EF, Kluijtmans LAJ, Heil SG, Trijbels JM, Eskes TK, Van Oppenraaij-Emmerzaal D, Banerjee R, Blom HJ (1997) Sequence analysis of the coding region of human methionine synthase: Relevance to hyperhomocysteinaemia in NTD and vascular disease. Q J Med 90:511–517CrossRefGoogle Scholar
- 31.Melse-Boonstra A, Lievers KJ, Blom HJ, Verhoef P (2004) Bioavailability of polyglutamyl folic acid relative to that of monoglutamyl folic acid in subjects with different genotypes of the glutamate carboxypeptidase II gene. Am J Clin Nutr 80:700–704Google Scholar
- 32.Rady PL, Szucs S, Grady J, Hudnall SD, Kellner LH, Nitowsky H, Tyring SK, Matalon RK (2002) Genetic polymorphisms of methylenetetrahydrofolate reductase (MTHFR) and methionine synthase reductase (MTRR) in ethnic populations in Texas; a report of a novel MTHFR polymorphic site, G1793A. Am J Med Genet 107:162–168CrossRefGoogle Scholar
- 35.Tsai MY, Bignell M, Schwichtenberg K, Hanson NQ (1996) High prevalence of a mutation in the cystathionine beta-synthase gene. Am J Hum Genet 59:1262–1267Google Scholar
- 38.Tan W, Miao X, Wang L, Yu C, Xiong P, Liang G, Sun T, Zhou Y, Zhang X, Li H, Lin D (2005) Significant increase in risk of gastroesophageal cancer is associated with interaction between promoter polymorphisms in thymidylate synthase and serum folate status. Carcinogenesis 26:1430–1435CrossRefGoogle Scholar
- 39.Ulrich CM, Bigler J, Velicer CM, Greene EA, Farin FM, Potter JD (2000) Searching expressed sequence tag databases: discovery and confirmation of a common polymorphism in the thymidylate synthase gene. Cancer Epidemiol Biomarkers Prev 9:1381–1385Google Scholar