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 du ring fasting or post-methionine load (PML), is recognized as a risk factor for coronary artery diseases (CAD). Cystathionine beta-synthase (CBS), a ke y enzyme in the transsulfuration pathway, is important for the metabolism o f homocysteine. In recent years, a relatively prevalent mutation, the 844in s68 (68-bp insertion), was found to be carried by about 12% of the general population. In the current investigation, we studied 741 individuals with r espect 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 fastin g and PML increase in tHcy levels were lower in individuals carrying the 84 4ins68 variant compared to those without the insertion; although only the d ifference in PML increase in tHcy reached statistical significance (P = 0.0 2). When these individuals were divided into two groups based on vitamin B- 6 concentration, the PML increase in tHcy was significantly lower in indivi duals heterozygous for the insertion compared to those without the insertio n only in the group of individuals whose vitamin B-6 concentrations were be low 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 lo w concentrations of pyridoxal-5'-phosphate, a cofactor of the CBS enzyme, ( C) 1999 Academic Press.