Trends in Pharmacological Sciences
ReviewBiological and clinical implications of the MTHFR C677T polymorphism
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)
Riboflavin as a determinant of plasma total homocysteine: effect modification by the methylenetetrahydrofolate reductase C677T polymorphism
Clin. Chem.
(2000)The controversy over homocysteine and cardiovascular risk
Am. J. Clin. Nutr.
(2000)- et al.
A common mutation in the methylenetetrahydrofolate reductase gene is associated with an accumulation of formylated tetrahydrofolates in red blood cells
Proc. Natl. Acad. Sci. USA
(1998) Determinants of plasma homocysteine
The C677T methylenetetrahydrofolate reductase gene mutation in hemodialysis patients
J. Am. Soc. Nephrol.
(2000)Hyperhomocysteinemia in hemodialysis patients: effects of 12-month supplementation with hydrosoluble vitamins
Kidney Int.
(2000)Maternal vitamin use, genetic variation of infant methylenetetrahydrofolate reductase, and risk for spina bifida
Am. J. Epidemiol.
(1998)Polymorphisms in genes involved in folate metabolism as maternal risk factors for Down syndrome
Am. J. Hum. Genet.
(2000)A common mutation in the 5,10-methylenetetrahydrofolate reductase gene as a new risk factor for placental vasculopathy
Am. J. Obstet. Gynecol.
(2000)677 C→T polymorphism of the methylenetetrahydrofolate reductase gene and preeclampsia
Obstet. Gynecol.
(2000)