Bringing individuality to public health recommendations

The data generated from the human genome project offers unprecedented opportunities to elucidate the etiology of chronic diseases and developmental anomalies that arise from deleterious genome-diet interactions. Folate metabolism is an attractive system to explore such relationships. Folate is necessary for the synthesis of purine and thymidine deoxyribonucleotides and S-adenosylmethionine, a cofactor required for DNA methylation. Impaired folate metabolism results from primary folate deficiency, alcohol, gastrointestinal disorders that result in malabsorption, single nucleotide polymorphisms, increased folate catabolism and secondary nutrient deficiencies in vitamin B-6, vitamin B-12 and iron arising from a variety of pathologies. Any of these conditions singly or in combination influence DNA synthesis, DNA integrity, allelic-specific gene expression, chromatin structure and DNA mutation rates. Biochemical manifestations of impaired folate metabolism include increased uracil uptake into DNA, altered DNA methylation status and elevated homocysteine and S-adenosylhomocysteine in serum and tissues. These biochemical changes are associated with risk for cancer, cardiovascular disease, neural tube defects and some neuropathies and anemia, although direct causative mechanisms have not been established in all cases. Interactions between folate and the genome are reciprocal; polymorphisms in key genes influence folate nutritional requirements, indicating that dietary folate adequacy likely exerts selective pressure and thereby influences genetic variation. Other studies indicate that exposure to excess folate, perhaps at levels that occur at the upper end of the intake distribution curve, may have unintended consequences in promoting embryo viability. Therefore individualizing folic acid dietary recommendations necessitates a detailed understanding of all genetic and physiological variables that influence the interaction of folate with the genome and their relationship to the disease process.