Review
Biological and clinical implications of the MTHFR C677T polymorphism

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Abstract

The enzyme methylenetetrahydrofolate reductase (MTHFR) directs folate species either to DNA synthesis or to homocysteine (Hcy) remethylation. The common MTHFR C677T polymorphism affects the activity of the enzyme and hence folate distribution. Under conditions of impaired folate status, the homozygous TT genotype has been regarded as harmful because it is associated with a high concentration of plasma total Hcy, increased risk of neural tube defects and colorectal neoplasias, and can also predispose individuals to adverse effects from drugs with antifolate effects. The MTHFR C677T polymorphism shows no consistent correlation with cardiovascular risk and longevity but, in combination with positive folate balance, the TT genotype is associated with decreased risk of colorectal neoplasias. Because of the high prevalence of this polymorphism in most populations, the TT variant might represent an ancestral genetic adaptation to living constraints (tissue injury or unbalanced vitamin intake) that has become a determinant of disease profiles in modern times.

Section snippets

Hcy and folate

Several reports have shown consistently that the T allele is associated with a high concentration of plasma tHcy. The effect on the concentration of tHcy is most pronounced in homozygous TT subjects with low folate concentrations 8. This is envisaged by a steeper slope of the curve of the inverse relationship between plasma tHcy and serum folate in subjects with the TT compared with the CC genotype 11, which suggests that the C677T transition confers increased folate responsiveness. In line

Disease

The relationship between the MTHFR C677T polymorphism and disease involves two aspects. First, the disease might influence tHcy concentrations and there might be effect modification by the MTHFR polymorphism. Second, the genotype might be associated with disease risk, possibly mediated by altered metabolism of folates and Hcy.

Drugs

Several drugs that interfere with folate status increase the concentration of tHcy (Ref. 18). Such drugs include not only the classical antifolate methotrexate, trimethoprim 52, but also sulfasalazine and the antiepileptic drugs phenytoin, carbamazepine and valproic acid.

In rheumatoid patients treated with methotrexate or sulfasalazine 53 and in epileptics receiving anticonvulsant medication 54, the tHcy concentrations are higher in TT than in CC subjects. In hypercholesterolemic children,

Concluding remarks and a hypothesis

The C677T transition has been implicated in several diseases. For neural tube defects and some malignant diseases, the TT genotype confers increased risk at low folate concentrations. At high folate concentrations, the TT genotype affords protection against colorectal neoplasias. However, despite intensive research, no conclusion has been reached regarding the association between the polymorphism and cardiovascular disease.

Thus, the MTHFR TT genotype appears to protect against some diseases and

Acknowledgements

Our work was supported by EU Commission Demonstration Project Contract BMH4-CT98-3549.

References (59)

  • J. Chen

    MTHFR polymorphism, methyl-replete diets and the risk of colorectal carcinoma and adenoma among US men and women: an example of gene–environment interactions in colorectal tumorigenesis

    J. Nutr.

    (1999)
  • A.J. Levine

    The methylenetetrahydrofolate reductase 677C→T polymorphism and distal colorectal adenoma risk

    Cancer Epidemiol. Biomarkers Prev.

    (2000)
  • Ulvik, A. et al. Smoking, folate and methylenetetrahydrofolate reductase status as interactive determinants of...
  • Y.I. Kim

    Methylenetetrahydrofolate reductase polymorphisms, folate, and cancer risk: a paradigm of gene–nutrient interactions in carcinogenesis

    Nutr. Rev.

    (2000)
  • L. Brattstrom

    A common methylenetetrahydrofolate reductase gene mutation and longevity

    Atherosclerosis

    (1998)
  • L.B. Bailey et al.

    Polymorphisms of methylenetetrahydrofolate reductase and other enzymes: metabolic significance, risks and impact on folate requirement

    J. Nutr.

    (1999)
  • S.-S. Kang

    Thermolabile defect of methylenetetrahydrofolate reductase in coronary artery disease

    Circulation

    (1993)
  • H. Refsum

    Homocysteine and cardiovascular disease

    Annu. Rev. Med.

    (1998)
  • R.H. Finnell

    Neural tube and craniofacial defects with special emphasis on folate pathway genes

    Crit. Rev. Oral Biol. Med.

    (1998)
  • J.G. Ray et al.

    Folic acid and homocyst(e)ine metabolic defects and the risk of placental abruption, pre-eclampsia and spontaneous pregnancy loss: a systematic review

    Placenta

    (1999)
  • P. Frosst

    Identification of a candidate genetic risk factor for vascular disease: a common mutation at the methylenetetrahydrofolate reductase locus

    Nat. Genet.

    (1995)
  • L. Brattstrom

    Common methylenetetrahydrofolate reductase gene mutation leads to hyperhomocysteinemia but not to vascular disease: the result of a meta-analysis

    Circulation

    (1998)
  • L.D. Botto et al.

    5,10-Methylenetetrahydrofolate reductase gene variants and congenital anomalies: a HuGE review

    Am. J. Epidemiol.

    (2000)
  • A.B. Guttormsen

    Determinants and vitamin responsiveness of intermediate hyperhomocysteinemia (≥40 μmol l−1). The Hordaland homocysteine study

    J. Clin. Invest.

    (1996)
  • M.R. Malinow

    The effects of folic acid supplementation on plasma total homocysteine are modulated by multivitamin use and methylenetetrahydrofolate reductase genotypes

    Arterioscler. Thromb. Vasc. Biol.

    (1997)
  • W.L. Nelen

    Methylenetetrahydrofolate reductase polymorphism affects the change in homocysteine and folate concentrations resulting from low dose folic acid supplementation in women with unexplained recurrent miscarriages

    J. Nutr.

    (1998)
  • A.M. Molloy

    Whole-blood folate values in subjects with different methylenetetrahydrofolate reductase genotypes: differences between the radioassay and microbiological assays

    Clin. Chem.

    (1998)
  • B.D. Guenther

    The structure and properties of methylenetetrahydrofolate reductase from Escherichia coli suggest how folate ameliorates human hyperhomocysteinemia

    Nat. Struct. Biol.

    (1999)
  • A. D'Angelo

    The role of vitamin B12 in fasting hyperhomocysteinemia and its interaction with the homozygous C677T mutation of the methylenetetrahydrofolate reductase (MTHFR) gene. A case-control study of patients with early-onset thrombotic events

    Thromb. Haemost.

    (2000)
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