Polymorphisms in the methylenetetrahydrofolate reductase gene: clinical consequences

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.