European Journal of Nutrition

, Volume 53, Issue 7, pp 1549–1559 | Cite as

MTHFR C677T genotype and cardiovascular risk in a general population without mandatory folic acid fortification

  • Lise Lotte N. Husemoen
  • Tea Skaaby
  • Torben Jørgensen
  • Betina H. Thuesen
  • Mogens Fenger
  • Niels Grarup
  • Camilla H. Sandholt
  • Torben Hansen
  • Oluf Pedersen
  • Allan Linneberg
Original Contribution



Meta-analyses have suggested an effect of MTHFR C677T genotype (rs1801133), a proxy for blood total homocysteine, on cardiovascular disease (CVD) in populations with low population dietary folate. The aim was to examine the association and effect modification by serum folate and vitamin B12 levels between MTHFR and CVD-related outcomes in a general population with no mandatory folic acid fortification policy.


The study population included 13,748 adults retrieved from pooling of four population-based studies conducted in Denmark. MTHFR genotype, serum folate (measured in approximately 9,356 individuals), and serum vitamin B12 (9,215 individuals), hypertension, and dyslipidemia were measured at baseline, and participants were followed for a mean of 10.5–11.7 years in central registries for diagnoses of stroke (623 incidents), ischaemic heart disease (IHD) (835 incidents), and all-cause mortality (1,272 incidents).


The MTHFR genotype (TT vs. CC/CT) was not associated with hypertension [OR (95 % CI) 1.09 (0.95–1.25)], dyslipidemia [OR (95 % CI) 0.97 (0.84–1.11)], stroke [HR (95 % CI) 0.92 (0.69–1.23)], and all-cause mortality [HR (95 % CI) 0.94 (0.77–1.14)], either overall, or in participants with low serum folate or B12 status (P values for interactions 0.15–0.94). Individuals with the MTHFR TT genotype had a higher risk of IHD (HR (95 % CI) 1.38 (1.11–1.71)), but this association was not modified by folate status (P value for interaction 0.45).


Our results do not support a causal relationship between homocysteine and CVD. However, we cannot exclude a direct causal effect of MTHFR C677T genotype on IHD.


Homocysteine Folate B12 Cardiovascular disease MTHFR rs1801133 



The present study was supported by grants from the Health Insurance Foundation (Grant No. 2010 B 131), and the Danish Agency for Science Technology and Innovation (Grant No. 2101-06-0065). The Novo Nordisk Foundation Center for Basic Metabolic Research is an independent Research Center at the University of Copenhagen partially funded by an unrestricted donation from the Novo Nordisk Foundation ( The study was partially funded by the Lundbeck Foundation (The Lundbeck Foundation Centre for Applied Medical Genomics in Personalised Disease Prediction, Prevention and Care (LuCamp),

Conflict of interest

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


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Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Lise Lotte N. Husemoen
    • 1
  • Tea Skaaby
    • 1
  • Torben Jørgensen
    • 1
    • 2
  • Betina H. Thuesen
    • 1
  • Mogens Fenger
    • 3
  • Niels Grarup
    • 4
  • Camilla H. Sandholt
    • 4
  • Torben Hansen
    • 4
    • 5
  • Oluf Pedersen
    • 4
    • 6
    • 7
    • 8
  • Allan Linneberg
    • 1
    • 2
    • 9
  1. 1.Research Centre for Prevention and Health, Glostrup University HospitalThe Capital Region of DenmarkGlostrupDenmark
  2. 2.Faculty of Health and Medical SciencesUniversity of CopenhagenCopenhagenDenmark
  3. 3.Department of Clinical BiochemistryCopenhagen Hvidovre University HospitalHvidovreDenmark
  4. 4.The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical SciencesUniversity of CopenhagenCopenhagenDenmark
  5. 5.Faculty of Health SciencesUniversity of Southern DenmarkOdenseDenmark
  6. 6.Faculty of Health SciencesAarhus UniversityAarhusDenmark
  7. 7.Hagedorn Research InstituteGentofteDenmark
  8. 8.Institute of Biomedical Science, Faculty of Health and Medical SciencesUniversity of CopenhagenCopenhagenDenmark
  9. 9.Department of Clinical Experimental ResearchGlostrup University HospitalGlostrupDenmark

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