5,10-Methylenetetrahydrofolate reductase (MTHFR) plays a key role in
folate metabolism by channeling one-
carbon units between
nucleotide synthesis and methylation reactions. Severe
enzyme deficiency leads to
hyperhomocysteinemia and
homocystinuria, with altered
folate distribution and a phenotype that is characterized by damage to the nervous and vascular systems. Two frequent polymorphisms in the human MTHFR gene confer moderate functional impairment of MTHFR activity for homozygous mutant individuals. The C to T change at
nucleotide position 677, whose functional consequences are dependent on
folate status, has been extensively studied for its clinical consequences. A second polymorphism, an A to C change at
nucleotide position 1298, is not as well characterized. Still equivocal are associations between MTHFR polymorphisms and vascular arteriosclerotic or thrombotic disease.
Neural tube defects and
pregnancy complications appear to be linked to impaired MTHFR function.
Colonic cancer and acute
leukemia, however, appear to be less frequent in individuals homozygous for the 677T polymorphism.MTHFR polymorphisms influence the
homocysteine-lowering effect of folates and could modify the pharmacodynamics of
antifolates and many other drugs whose metabolism, biochemical effects, or target structures require methylation reactions. However, only preliminary evidence exists for gene-drug interactions. This review summarizes the biochemical basis and clinical evidence for interactions between MTHFR polymorphisms and several disease entities, as well as potential interactions with
drug therapies. Future investigations of MTHFR in disease should consider the influence of other variants of functionally-related genes as well as the medication regimen of the patients. Animal models for genetic deficiencies in
folate metabolism will likely play a greater role in our understanding of
folate-dependent disorders.