Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Folic acid — vitamin and panacea or genetic time bomb?

Abstract

We live in a health-conscious age — many of us supplement our diet with essential micronutrients through the discretionary use of multivitamin pills or judicious selection of foods that have a health benefit beyond that conferred by the nutrient content alone — the so-called 'functional foods'. Indeed, the citizens of some nations have little choice, with a mandatory fortification policy in place for certain vitamins. But do we ever stop to consider the consequences of an increased exposure to micronutrients? We examine this issue in relation to the B-group vitamin folic acid, and ask whether supplementation with this vitamin could introduce a strong genetic selection pressure — one that has the side effect of increasing the prevalence of some of the most significant, human life-threatening diseases. Are we affecting our genetics — is this a case of human evolution in progress by altering our diet?

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: The putative cellular mechanism for genetic selection that is based on folate gene variant and dietary folate.
Figure 2: Cellular effect of excess synthetic folate.

References

  1. 1

    Gillies, P. J. Nutrigenomics: the Rubicon of molecular nutrition. J. Am. Diet. Assoc. 103, S50–S55 (2003).

    Article  Google Scholar 

  2. 2

    Muller, M. & Kersten, S. Nutrigenomics: goals and strategies. Nature Rev. Genet. 4, 315–322 (2003).

    Article  Google Scholar 

  3. 3

    Kaput, J. Diet–disease gene interactions. Nutrition 20, 26–31 (2004).

    CAS  Article  Google Scholar 

  4. 4

    Lucock, M. Is folic acid the ultimate functional food component for disease prevention? BMJ 328, 211–214 (2004).

    CAS  Article  Google Scholar 

  5. 5

    Godfrey, P. S. A. et al. Enhancement of recovery from psychiatric illness by methylfolate. Lancet 336, 392–395 (1990).

    CAS  Article  Google Scholar 

  6. 6

    Clarke, R. et al. Folate, vitamin B12, and serum total homocysteine levels in confirmed Alzheimer disease. Arch. Neurol. 55, 1449–1455 (1998).

    CAS  Article  Google Scholar 

  7. 7

    Slattery, M. L., Potter, J. D., Samowitz, W., Schaffer, D. & Leppert, M. Methylenetetrahydrofolate reductase, diet, and risk of colon cancer. Cancer Epidemiol. Biomarkers Prev. 8, 513–518 (1999).

    CAS  PubMed  Google Scholar 

  8. 8

    Zhang, S. et al. A prospective study of folate intake and the risk of breast cancer. JAMA 281, 1632–1637 (1999).

    CAS  Article  Google Scholar 

  9. 9

    Stolzenberg-Solomon, R. Z. et al. Dietary and other methyl-group availability factors and pancreatic cancer risk in a cohort of male smokers. Am. J. Epidemiol. 153, 680–687 (2001).

    CAS  Article  Google Scholar 

  10. 10

    Butterworth, C. E. Folate status, women's health, pregnancy outcome and cancer. J. Am. Coll. Nutr. 12, 438–441 (1993).

    Article  Google Scholar 

  11. 11

    Kamei, T. et al. Experimental study of the therapeutic effects of folate, vitamin A and vitamin B12 on squamous metaplasia of the bronchial epithelium. Cancer 71, 2477–2483 (1993).

    CAS  Article  Google Scholar 

  12. 12

    Skibola, C. F. et al. Polymorphisms in the methylenetetrahydrofolate reductase gene are associated with susceptibility to acute leukemia in adults. Proc. Natl Acad. Sci. USA 96, 12810–12815 (1999).

    CAS  Article  Google Scholar 

  13. 13

    Boushey, C. J., Beresford, S. A., Omenn, G. S. & Motulsky, A. G. A quantitative assessment of plasma homocysteine as a risk factor for vascular disease. Probable benefits of increasing folic acid intakes. JAMA 274, 1049–1057 (1995).

    CAS  Article  Google Scholar 

  14. 14

    Medical Research Council Vitamin Study Group. Prevention of neural tube defects: results of the Medical Research Council Vitamin Study. Lancet 338, 131–137 (1991).

  15. 15

    James, S. J. et al. Abnormal folate metabolism and mutation in the methylenetetrahydrofolate reductase gene may be maternal risk factors for Down's syndrome. Am. J. Clin. Nutr. 70, 495–501 (1999).

    CAS  Article  Google Scholar 

  16. 16

    Dekker, G. A. et al. Underlying disorders associated with severe early onset preeclampsia. Am. J. Obstet. Gynecol. 173, 1042–1048 (1995).

    CAS  Article  Google Scholar 

  17. 17

    Rajkovic, A., Catalano, P. M. & Malinow, M. R. Elevated homocyst(e)ine levels with preeclampsia. Obstet. Gynecol. 90, 168–171 (1997).

    CAS  Article  Google Scholar 

  18. 18

    Roberts, D. & Schwartz, R. S. Clotting and hemorrhage in the placenta — a delicate balance. N. Engl. J. Med. 347, 57–59 (2002).

    Article  Google Scholar 

  19. 19

    Wong, W. Y. et al. Effects of folic acid and zinc sulfate on male factor subfertility: a double-blind, randomized, placebo-controlled trial. Fertil. Steril. 77, 491–498 (2002).

    Article  Google Scholar 

  20. 20

    Friso, S. & Choi, S. W. Gene-nutrient interactions and DNA methylation. J. Nutr. 132, S2382–S2387 (2002).

    Article  Google Scholar 

  21. 21

    Duthie, S. J. & Hawdon, A. DNA instability (strand breakage, uracil misincorporation, and defective repair) is increased by folic acid depletion in human lymphocytes in vitro. FASEB J. 12, 1491–1497 (1998).

    CAS  Article  Google Scholar 

  22. 22

    Lucock, M. et al. A critical role for B-vitamin nutrition in human developmental and evolutionary biology. Nutr. Res. 23, 1463–1475 (2003).

    CAS  Article  Google Scholar 

  23. 23

    US Food and Drug Administration. Food standards: amendment of standards of identity for enriched grain products to require addition of folic acid. Final rule. Fed. Regist. 61, 8781–8797 (1996).

  24. 24

    Lewis, C. J., Crane, N. T., Wilson, D. B. & Yatley, E. A. Estimated folate intakes: data updated to reflect food fortification, increased bioavailability, and dietary supplement use. Am. J. Clin. Nutr. 70, 198–207 (1999).

    CAS  Article  Google Scholar 

  25. 25

    Isotalo, P. A., Wells, G. A. & Donnelly, J. G. Neonatal and fetal methylenetetrahydrofolate reductase genetic polymorphisms: an examination of C677T and A1298C mutations. Am. J. Hum. Genet. 67, 986–990 (2000).

    CAS  Article  Google Scholar 

  26. 26

    Munoz-Moran, E. et al. Genetic selection and folate intake during pregnancy. Lancet 352, 1120–1121 (1998).

    CAS  Article  Google Scholar 

  27. 27

    Nelen, W. L., Steegers, E. A., Eskes, T. K. & Blom, H. J. Genetic risk factor for unexplained recurrent early pregnancy loss. Lancet 350, 861 (1997).

    CAS  Article  Google Scholar 

  28. 28

    Gris, J. C. et al. Case-control study of the frequency of thrombophilic disorders in couples with late foetal loss and no thrombotic antecedent — the Nimes Obstetricians and Haematologists Study 5 (NOHA5). Thromb. Haemost. 81, 891–899 (1999).

    CAS  Article  Google Scholar 

  29. 29

    Wouters, M. G. et al. Hyperhomocysteinemia: a risk factor in women with unexplained recurrent early pregnancy loss. Fertil. Steril. 60, 820–825 (1993).

    CAS  Article  Google Scholar 

  30. 30

    Rosenberg, N. et al. The frequent 5,10-methylenetetrahydrofolate reductase C677T polymorphism is associated with a common haplotype in whites, Japanese, and Africans. Am. J. Hum. Genet. 70, 758–762 (2002).

    CAS  Article  Google Scholar 

  31. 31

    Botto, L. D. & Yang, Q. 5,10-Methylenetetrahydrofolate reductase gene variants and congenital abnormalities: a HuGE review. Am. J. Epidimiol. 151, 862–877 (2000).

    CAS  Article  Google Scholar 

  32. 32

    Sohn, K. J., Croxford, R., Yates, Z., Lucock, M. & Kim, Y. I. The effect of the methylenetetrahydrofolate reductase C677T polymorphism on chemosensitivity of colon and breast cancer cells to 5-fluorouracil and methotrexate. J. Natl Cancer Inst. 96, 134–144 (2004).

    CAS  Article  Google Scholar 

  33. 33

    Eskes, T. K. Homocysteine and human reproduction. Clin. Exp. Obstet. Gynecol. 27, 157–167 (2000).

    CAS  PubMed  Google Scholar 

  34. 34

    Ratanasthien, K., Blair, J. A., Leeming, R. J., Cooke, W. T. & Melikian, V. Serum folates in man. J. Clin. Pathol. 30, 438–448 (1977).

    CAS  Article  Google Scholar 

  35. 35

    Kelly, P., McPartlin, J., Goggins, M., Weir, D. G. & Scott, J. M. Unmetabolised folic acid in serum: acute studies in subjects consuming fortified food and supplements. Am. J. Clin. Nutr. 65, 1790–1795 (1997).

    CAS  Article  Google Scholar 

  36. 36

    Lucock, M. D., Wild, J., Smithells, R. & Hartley, R. In vivo characterisation of the absorption and biotransformation of pteroylglutamic acid in man: a model for future studies. Biochem. Med. Metab. Biol. 42, 30–42 (1989).

    CAS  Article  Google Scholar 

  37. 37

    Yates, Z. & Lucock, M. Methionine synthase polymorphism A2756G is associated with susceptibility for thromboembolic events and altered B vitamin/thiol metabolism. Haematologica 87, 751–756 (2002).

    CAS  PubMed  Google Scholar 

  38. 38

    Lucock, M. D. et al. Optimisation of chromatographic conditions for the determination of folates in foods and biological tissues for nutritional and clinical work. Food Chem. 53, 329–338 (1995).

    CAS  Article  Google Scholar 

  39. 39

    Guy, M. et al. Vitamin D receptor gene polymorphisms and breast cancer risk. Clin. Cancer. Res. 10, 5472–5481 (2004).

    CAS  Article  Google Scholar 

  40. 40

    Jablonski, N. G. & Chaplin, G. J. The evolution of human skin coloration. Hum. Evol. 39, 57–106 (2000).

    CAS  Article  Google Scholar 

  41. 41

    Loomis, W. F. Skin-pigment regulation of vitamin–D biosynthesis in man. Science 157, 501–506 (1967).

    CAS  Article  Google Scholar 

  42. 42

    Aoki, K. Sexual selection as a cause of human skin colour variation: Darwin's hypothesis revisited. Ann. Hum. Biol. 29, 589–608 (2002).

    Article  Google Scholar 

  43. 43

    Pennisi, E. Evolution of developmental diversity: evo-devo devotees eye ocular origins and more. Science 296, 1010–1011 (2002).

    CAS  Article  Google Scholar 

  44. 44

    Xu, D. X. et al. The associations among semen quality, oxidative DNA damage in human spermatozoa and concentrations of cadmium, lead and selenium in seminal plasma. Mutat. Res. 534, 155–163 (2003).

    CAS  Article  Google Scholar 

  45. 45

    Davis, C. D., Uthus, E. O. & Finley, J. W. Dietary selenium and arsenic affect DNA methylation in vitro in Caco–2 cells and in vivo in rat liver and colon. J. Nutr. 130, 2903–2909 (2000).

    CAS  Article  Google Scholar 

  46. 46

    El-Bayoumy, K. The protective role of selenium on genetic damage and on cancer. Mutat. Res. 475, 123–139 (2001).

    CAS  Article  Google Scholar 

  47. 47

    Ma, J. et al. Methylenetetrahydrofolate reductase polymorphism, dietary interractions and risk of colorectal cancer. Cancer Res. 57, 1098–1102 (1997).

    CAS  Google Scholar 

  48. 48

    Lucock, M. D. & Yates, Z. in Folate and Human Development (ed. Massaro, E. J.) 263–298 (Humana, Totowa, New Jersey, 2001).

    Google Scholar 

  49. 49

    Frosst, P. et al. A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nature Genet. 10, 111–113 (1995).

    CAS  Article  Google Scholar 

  50. 50

    Kang, S. -S. et al. Thermolabile methylenetetrahydrofolate reductase: an inherited risk factor for coronary heart disease. Am. J. Hum. Genet. 48, 536–545 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. 51

    Mills, J. L. et al. Methylenetetrahydrofolate reductase thermolabile variant and oral cleft. Am. J. Med. Genet. 86, 71–74 (1999).

    CAS  Article  Google Scholar 

  52. 52

    Van der Put, N. M. J. et al. Mutated methylenetetrahydrofolate reductase as a risk factor for spina bifida. Lancet 346, 1070–1071 (1995).

    CAS  Article  Google Scholar 

  53. 53

    Guenther, B. D. et al. The structure and properties of methylenetetrahydrofolate reductase from Escherichia coli suggest how folate ameliorates human hyperhomocysteinemia. Nature Struct. Biol. 6, 359–365 (1999).

    CAS  Article  Google Scholar 

  54. 54

    Matthews, R. G. & Baugh, C. M. Interactions of pig liver methylenetetrahydrofolate reductase with methylenetetrahydropteroylpolyglutamate substrates and with dihydropteroylpolyglutamate inhibitors. Biochemistry 19, 2040–2045 (1980).

    CAS  Article  Google Scholar 

  55. 55

    Lucock, M. et al. The impact of phenylketonuria on folate metabolism. Mol. Genet. Metab. 76, 305–312 (2002).

    CAS  Article  Google Scholar 

  56. 56

    Hustad, S. et al. Riboflavin as a determinant of plasma total homocysteine: effect modification by the methylenetetrahydrofolate reductase C677T polymorphism. Clin. Chem. 46, 1065–1071 (2002).

    Google Scholar 

  57. 57

    Shimakawa, T. et al. Vitamin intake: a possible determinant of plasma homocyst(e)ine among middle-aged adults. Ann. Epidemiol. 7, 285–293 (1997).

    CAS  Article  Google Scholar 

  58. 58

    Jacques, P. F. et al. The relationship between riboflavin and plasma total homocysteine in the Framingham Offspring cohort is influenced by folate status and the C677T transition in the methylenetetrahydrofolate reductase gene. J. Nutr. 132, 283–288 (2002).

    CAS  Article  Google Scholar 

  59. 59

    McNulty, H. et al. Impaired functioning of thermolabile methylenetetrahydrofolate reductase is dependent on riboflavin status: implications for riboflavin requirements. Am. J. Clin. Nutr. 76, 436–441 (2002).

    CAS  Article  Google Scholar 

  60. 60

    Bird, A. The essentials of DNA methylation. Cell 70, 5–8 (1992).

    CAS  Article  Google Scholar 

  61. 61

    Antequera, F. & Bird, A. Number of CpG islands and genes in human and mouse. Proc. Natl Acad. Sci. USA 90, 11995–11999 (1993).

    CAS  Article  Google Scholar 

  62. 62

    Bird, A., Taggart, M., Frommer, M., Miller, O. J. & Macleod, D. A fraction of the mouse genome that is derived from islands of nonmethylated, CpG-rich DNA. Cell 40, 91–99 (1985).

    CAS  Article  Google Scholar 

  63. 63

    Arlt, M. F., Casper, A. M. & Glover, T. W. Common fragile sites. Cytogenet. Genome Res. 100, 92–100 (2003).

    CAS  Article  Google Scholar 

  64. 64

    Choi, S. W., Kim, Y. I., Weitzel, J. N. & Mason, J. B. Folate depletion impairs DNA excision repair in the colon of the rat. Gut 43, 93–99 (1998).

    CAS  Article  Google Scholar 

  65. 65

    Gu, L., Wu, J., Oiu, L., Jennings, C. D. & Li, G. M. Involvement of DNA mismatch repair in folate deficiency-induced apoptosis. J. Nutr. Biochem. 13, 355–363 (2002).

    CAS  Article  Google Scholar 

  66. 66

    Johanning, G. L. Wenstrom, K. D. & Tamura, T. Changes in frequencies of heterozygous thermolabile 5,10-methylenetetrahydrofolate reductase gene in fetuses with neural tube defects. J. Med. Genet. 39, 366–367 (2002).

    CAS  Article  Google Scholar 

Download references

Acknowledgements

We acknowledge the support that was provided by the British Heart Foundation. Z.Y. was a British Heart Foundation Ph.D. scholar, and this work was carried out at the School of Medicine, University of Leeds, United Kingdom and the School of Applied Sciences, University of Newcastle, Australia.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Mark Lucock.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Related links

Related links

DATABASES

OMIM

Alzheimer disease

Down syndrome

FURTHER INFORMATION

Mark Lucock's web page

Glossary

ADMIXTURE

Gene flow between differentiated populations.

HIGH-PRESSURE LIQUID CHROMATOGRAPHY

(HPLC). A rapid variant of column chromatography used for high-resolution separation of molecules of low-to-moderate molecular weight.

KM VALUES

The affinity of enzymes for a substrate.

PRE-ECLAMPSIA

Also known as toxaemia, it is a condition that can occur in a woman in the second half of her pregnancy that causes high blood pressure, protein in the urine, blood changes and other problems such as low birth weight.

SPINA BIFIDA

A condition that occurs at birth in which part of the spinal cord protrudes through a small indentation in the spinal column resulting in partial to total loss of voluntary movement in the lower body.

TERATOGENIC

A factor that causes malformation of an embryo.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Lucock, M., Yates, Z. Folic acid — vitamin and panacea or genetic time bomb?. Nat Rev Genet 6, 235–240 (2005). https://doi.org/10.1038/nrg1558

Download citation

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing