Genetic polymorphisms in methyl-group metabolism and epigenetics: lessons from humans and mouse models

Abstract

Choline is an essential nutrient that is critical during fetal brain development. Choline deficiency, through disturbing methyl metabolism, may alter DNA methylation and thereby influence neural precursor cell proliferation and apoptosis. This results in long term alterations in brain structure and function, specifically memory function. A recommended dietary intake for choline in humans was set in 1998, and a portion of the choline requirement can be met via endogenous de novo synthesis of phosphatidylcholine catalyzed by phosphatidylethanolamine N-methyltransferase (PEMT) in the liver. Though many foods contain choline, many humans do not get enough in their diets. When deprived of dietary choline, most adult men and postmenopausal women developed signs of organ dysfunction (fatty liver, liver or muscle cell damage). However, only a portion of premenopausal women developed such problems. The difference in requirement occurs because estrogen induces expression of the PEMT gene and allows premenopausal women to make more of their needed choline endogenously. In addition, there is significant variation in the dietary requirement for choline that can be explained by common genetic variants (single nucleotide polymorphisms; SNPs) in genes of choline and folate metabolism. Some of these increase the risk of choline deficiency many-fold. These variations in choline requirement could have important implications for brain development.

Figure 1

Common genetic polymorphisms in choline and folate metabolism The pathways described are all present in the liver, with other tissues having one or more of these pathways. Each of the genes indicated in italics have single nucleotide polymorphisms that are described in the text. Some of these increase dietary choline requirements (effect on observed risk of choline deficiency (see text) noted next to gene name). PEMT = phosphatidylethanolamine-N-methyltransferase; CHDH = choline dehydrogenase; BHMT = betaine homocysteine methyltransferase; MTHFR = methylene tetrahydrofolate reductase; MTHFD1 = methylene tetrahydrofolate dehydrogenase; DMG = dimethylglycine; THF = tetrahydrofolate; SNP = single nucleotide polymorphism.