The basis of differential responses to folic acid supplementation

J Nutrigenet Nutrigenomics. 2011;4(2):99-109. doi: 10.1159/000327768. Epub 2011 May 28.


Background/aims: Elevated levels of total homocysteine (tHcy) are associated with an increased risk of many common diseases. Supplementation with folic acid has been shown to significantly reduce tHcy levels. We used the classical twin model to partition the variability in changes in plasma tHcy levels through folic acid supplementation into genetic, environmental, and confounding epidemiological factors.

Methods: We carried out an intervention study of folic acid using 101 healthy, female, identical and non-identical twins aged 50-80 years. Each twin was administered folic acid (0.8 mg/day) for 6 weeks. Total plasma folate, cobalamin and tHcy were measured at both baseline and after dosing. We calculated the heritability and tested for associations between the MTHFR C677T functional variant and response to folic acid supplementation.

Results: Supplementation with folic acid led to a significant reduction in tHcy levels. The mean tHcy changed from 12.14 to 10.42 μmol/l after supplementation (p < 10(-5)). Moreover, the change in tHcy levels was highly heritable (64%), not associated with the C677T functional variant at MTHFR and not confounded by age, BMI or diet.

Conclusions: Our results highlight the need to identify genetic factors associated with biomarkers of response to folate supplementation.

Publication types

  • Research Support, Non-U.S. Gov't
  • Twin Study

MeSH terms

  • Aged
  • Aged, 80 and over
  • Female
  • Folic Acid / administration & dosage*
  • Folic Acid / blood
  • Genetic Predisposition to Disease
  • Homocysteine / blood
  • Humans
  • Hyperhomocysteinemia / blood
  • Hyperhomocysteinemia / drug therapy*
  • Hyperhomocysteinemia / genetics
  • Methylenetetrahydrofolate Reductase (NADPH2) / genetics
  • Middle Aged
  • Models, Genetic
  • Nutrigenomics
  • Polymorphism, Single Nucleotide
  • Twins, Dizygotic
  • Twins, Monozygotic
  • Vitamin B 12 / blood


  • Homocysteine
  • Folic Acid
  • Methylenetetrahydrofolate Reductase (NADPH2)
  • Vitamin B 12