Polygenic influence on plasma homocysteine: association of two prevalent mutations, the 844ins68 of cystathionine β-synthase and A2756G of methionine synthase, with lowered plasma homocysteine levels

A moderately elevated plasma total homocysteine (tHcy), whether measured during fasting or post-methionine load (PML), is increasingly being recognized as a risk factor for coronary artery diseases (CAD). However, etiologies for moderately elevated plasma tHcy, particularly with regard to the role of genetic influence on plasma tHcy levels, are still not well understood. In the current investigation, we studied 1025 individuals with respect to the effect of the 68-bp insertion (844ins68 variant) of the cystathionine β-synthase (CBS) gene, the A2756G transition of the B12-dependent methionine synthase (MS) gene and the C677T transition of the methylenetetrahydrofolate reductase (MTHFR) gene on fasting and 4 h PML tHcy. Of these individuals, 153 (14.9%) were heterozygous for the 68-bp insertion, 329 (32.1%) were heterozygous for the G2756 allele and 122 (11.9%) were homozygous for the C677T transition. Individuals heterozygous for the insertion had significantly lower PML increase in tHcy concentrations, while individuals homozygous for the A2756G transition had significantly lower fasting tHcy levels. A 2-way ANOVA showed that there was no interaction between the 844ins68 and the A2756G 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 polygenic regulation of plasma tHcy. Overall, >50% of all individuals in this study carried polymorphic traits, which predisposed them to either higher or lower plasma tHcy concentrations, thus providing new evidence of the importance of genetic influences as determinants of tHcy levels.