Folate and Genetics

Inborn errors of folate/homocysteine metabolism are rare disorders that lead to a wide variety of developmental, neurological, and vascular complications; this group of disorders (homocystinurias) have been recognized for several decades. More recently, however, common mutations (or polymorphisms) in enzymes of folate metabolism have become identified as potential risk modifiers of several multifactorial disorders including neural tube defects, pregnancy complications, vascular disease, and cancer. The first and best characterized of this group of variants is an alanine‐to‐valine substitution at bp 677 of the enzyme methylenetetrahydrofolate reductase (MTHFR) which synthesizes the folate derivative for homocysteine remethylation to methionine. This variant, present in the homozygous state in 10% ‐ 15% of many North American, European, and Asian populations, results in mild hyperhomocysteinemia predominantly when folate status is low; this observation alludes to an increased requirement for folate in mutant individuals. The clinical impact of this variant, as well as a brief description of other variants in folate/homocysteine metabolism, will be discussed. In more recent work, we generated a mouse model with MTHFR deficiency, in order to address the genetic‐nutrient interactive effect and the biologic consequences of a disruption of folate metabolism. These mice have hyperhomocysteinemia, altered methylation, and enhanced utilization of choline/betaine to increase methionine biosynthesis. In addition, the mice appear to be quite useful as animal models for some of the above‐mentioned clinical disorders.