Polygenic influence on plasma homocysteine: association of two prevalent mutations, the 844ins68 of cystathionine beta-synthase and A(2756)G of methionine synthase, with lowered plasma homocysteine levels

A moderately elevated plasma total homocysteine (tHcy), whether measured du ring fasting or post-methionine load (PML), is increasingly being recognize d as a risk factor for coronary artery diseases (CAD). However, etiologies for moderately elevated plasma tHcy, particularly with regard to the role o f genetic influence on plasma tHcy levels, are still not well understood. I n the current investigation, we studied 1025 individuals with respect to th e effect of the 68-bp insertion (844ins68 variant) of the cystathionine bet a-synthase (CBS) gene, the A(2756)G transition of the B-12-dependent methio nine synthase (MS) gene and the C677T transition of the methylenetetrahydro folate reductase (MTHFR) gene on fasting and 4 h PML tHcy. Of these individ uals, 153 (14.9%) were heterozygous for the 68-bp insertion, 329 (32.1%) we re heterozygous for the G(2756) allele and 122 (11.9%) were homozygous for the C677T transition. Individuals heterozygous for the insertion had signif icantly lower PML increase in tHcy concentrations, while individuals homozy gous for the A(2756)G transition had significantly lower fasting tHcy level s. A 2-way ANOVA showed that there was no interaction between the 844ins68 and the A(2756)G transition for either fasting tHcy or PML increase in tHcy , confirming the fact that the effect of these two genotypes on plasma tHcy levels are additive. The effects are opposite but additive with the C677T genotype of the MTHFR gene. In conclusion, we document evidence of polygeni c regulation of plasma tHcy. Overall, > 50% of all individuals in this stud y carried polymorphic traits, which predisposed them to either higher or lo wer plasma tHcy concentrations, thus providing new evidence of the importan ce of genetic influences as determinants of tHcy levels. (C) 2000 Elsevier Science Ireland Ltd. All rights reserved.