European Journal of Nutrition

, Volume 56, Issue 1, pp 247–260 | Cite as

The impact of MTHFR 677 C/T genotypes on folate status markers: a meta-analysis of folic acid intervention studies

  • Natalie J. ColsonEmail author
  • Helen L. Naug
  • Elham Nikbakht
  • Ping Zhang
  • Joanna McCormack
Original Contribution



Methylenetetrahydrofolate reductase (MTHFR) is a key folate pathway enzyme with the T variant of the MTHFR gene increasing the risk of low folate status, particularly coupled with low folate intake. As genetic variability of MTHFR influences folate status, it is important to ensure an adequate intake that overrides genetic effects but minimises any adverse effects. Our aim was to assess the influence of MTHFR genotype on folate status followed by response to supplementation.


We performed a meta-analysis of ten folate intervention studies to assess the degree to which MTHFR C677T genotype influenced plasma homocysteine and serum folate levels as measures of folate status. We then examined response after supplementation at intake values up to the upper tolerable limit.


The MTHFR 677TT genotype was associated with higher plasma homocysteine (2.7 μmol/L, TT vs. CT/CC; 2.8 μmol/L, TT vs. CC) and lower serum folate (2.5 nmol/L, TT vs. CT/CC; 3.6 nmol/L, TT vs. CC). In two studies, the TT groups had mean plasma Hcy >15 μmol/L. Serum folate levels were >7 nmol/L for all genotype groups. After supplementation of 400 up to 1670 μg DFEs of folic acid or folic acid + fortified foods and/or natural food folates for a minimum of 4 weeks, there were no significant differences in plasma homocysteine levels; however, individuals with the TT genotype had a lower serum folate response to supplementation (7.2 nmol/L, TT vs. CT/CC; 8.7 nmol/L, TT vs. CC).


This meta-analysis confirms observations from observational and intervention studies that MTHFR TT genotype is associated with increased plasma homocysteine and lowered serum folate and less response to short-term supplementation. The results can be used for modelling and guiding personalised intake recommendations for the nutrient folate.


Folate Folic acid Homocysteine MTHFR 


Compliance with ethical standards

Conflict of interest

On behalf of all authors, the corresponding author states that there is no conflict of interest.

Supplementary material

394_2015_1076_MOESM1_ESM.docx (42 kb)
Supplementary material 1 (DOCX 42 kb)
394_2015_1076_MOESM2_ESM.docx (40 kb)
Supplementary material 2 (DOCX 39 kb)


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Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • Natalie J. Colson
    • 1
    • 2
    Email author
  • Helen L. Naug
    • 1
    • 2
  • Elham Nikbakht
    • 1
    • 2
  • Ping Zhang
    • 2
  • Joanna McCormack
    • 3
  1. 1.School of Medical ScienceGriffith UniversityGold CoastAustralia
  2. 2.Menzies Health Institute QueenslandGold CoastAustralia
  3. 3.School of Allied HealthGriffith UniversityGold CoastAustralia

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