The role of genetic variants of enzymes of folate/homocysteine metabolism in human disease. Folate is an essential vitamin that participates in many biochemical reactions that are important for a number of key biological processes. These include the methylation of substrates such as DNA, proteins and drugs, and the synthesis of purines and pyrimidines. Inadequate intake of folate or altered proportional distribution of the various intracellular forms of folate, together with elevated levels of the amino acid homocysteine, which requires folate to be methylated to methionine, have been associated with many major human pathologies ranging from neural tube defects (NTDs) to cardiovascular disease. For most such pathologies it is unclear whether it is inadequate folate or high homocysteine that is the pathogenic agent. We are studying the effect of functional polymorphisms of the enzymes that control folate/homocysteine metabolism to determine their impact on folate/homocysteine phenotype. Recently we have developed a cell culture model of low folate stress in order to investigate the changes in cell morphology, proliferation, and gene expression that are elicited by the perturbations in folate/homocysteine metabolism that are elicited by genetic, nutritional and pharmacologic variables. This work has the potential to identify products that are involved in disease pathogenesis and that may have functional polymorphisms that promote disease and/or alter drug responses.