The importance of (early) folate status to primary and secondary coronary artery disease prevention.

Folate, methionine, betaine, choline, zinc and Vitamins B(12), B(6) and B(2) are involved in one-carbon metabolism, which includes S-adenosylmethionine (SAM) substrated methylation. Inadequate enzyme activities and imbalances of substrates and cofactors in one-carbon metabolism, together referred to as the 'methyldietary' constituents, may cause homocysteine and S-adenosylhomocysteine accumulation. Hyperhomocysteinemia is associated with many disorders including coronary artery disease (CAD). CAD at adult age is also associated with low birth weight-induced 'programming', which prepares for unfavorable postpartum conditions and carries the potential of transgenerational transmission. CAD risks of hyperhomocysteinemia and 'programming' might find a common biochemical basis in epigenetics, which, among others, operates via SAM-substrated methylation of DNA and histones. Folic acid-responsive global and locus-specific hypomethylation were found in hyperhomocysteinemia and CAD. Currently, there is no hard evidence that folic acid supplementation of CAD patients is beneficial or that improved folate status in pregnancy prevents CAD in the offspring at adult age. The folate RDA as derived from CAD primary prevention might require embracement of the assumption that 'what nutritional measures are best for CAD patients are most probably best for the general population'. We have no knowledge on the optimal 'methyldiet' balance on which our genome has become adapted during millions of years of evolution and on which our genome consequently functions best. More insight may derive from the study of methyldietary constituents and soft endpoints such as plasma homocysteine and gene methylation, in healthy, pregnant and non-pregnant, subjects and CAD patients and in populations with high and low CAD risks and those consuming diets more closely related to our ancient diet. Folic acid supplementation is obviously unnecessary at sufficient intake of naturally occurring folates, implying that continuing efforts should aim at meeting the recommendations by making the right choice of food products, that are either or not folate-enriched by genetic modification.