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Relation between plasma homocysteine concentration, the 844ins68 variant of the cystathionine beta-synthase gene, and pyridoxal-5'-phosphate concentration.

A moderately elevated plasma total homocysteine (tHcy), whether measured during fasting or post-methionine load (PML), is recognized as a risk factor for coronary artery diseases (CAD). Cystathionine beta-synthase (CBS), a key enzyme in the transsulfuration pathway, is important for the metabolism of homocysteine. In recent years, a relatively prevalent mutation, the 844ins68 (68-bp insertion), was found to be carried by about 12% of the general population. In the current investigation, we studied 741 individuals with respect to the effect of the 68-bp insertion of the CBS gene on fasting and PML tHcy, and also determined the level of pyridoxal-5'-phosphate (vitamin B(6)), a cofactor of the CBS enzyme. Our results showed that the mean fasting and PML increase in tHcy levels were lower in individuals carrying the 844ins68 variant compared to those without the insertion; although only the difference in PML increase in tHcy reached statistical significance (P = 0.02). When these individuals were divided into two groups based on vitamin B(6) concentration, the PML increase in tHcy was significantly lower in individuals heterozygous for the insertion compared to those without the insertion only in the group of individuals whose vitamin B(6) concentrations were below the sample median (38.0 nmol/L). We speculate that the 68-bp insertion is associated with somewhat higher levels of CBS enzyme activity, and that the effect of this becomes more pronounced in the presence of relatively low concentrations of pyridoxal-5'-phosphate, a cofactor of the CBS enzyme.