Polymorphisms in the transcobalamin gene: association with plasma homocysteine in healthy individuals and vascular disease patients.

BACKGROUND: Hyperhomocysteinemia is an independent risk factor for cardiovascular disease (CVD). Intracellular vitamin B(12) deficiency may lead to increased plasma total homocysteine (tHcy) concentrations and because transcobalamin (TC) is the plasma transporter that delivers vitamin B(12) to cells, genetic variation in the TC gene may affect intracellular vitamin B(12) availability and, consequently, tHcy concentrations. METHODS: We examined five sequence variants, i.e., I23V, G94S, P259R, S348F, and R399Q, in the TC gene as possible determinants of tHcy and, concordantly, as possible risk factors for CVD in 190 vascular disease patients and 601 controls. We also studied potential effect-modification of vitamin B(12) by genotype. RESULTS: In individuals with high vitamin B(12), 259PP individuals had lower tHcy concentrations than 259PR and 259RR individuals. Homozygous 23VV individuals had lower fasting tHcy concentrations than their 23IV and 23II peers. None of the genotypes defined by the three other sequence variants showed an association with tHcy concentrations, nor was any TC genotype associated with an increased CVD risk. CONCLUSIONS: In individuals in the highest quartile of the vitamin B(12) distribution (>299 pmol/L), tHcy concentrations are lower in 259PP homozygotes than in 259PR and 259RR individuals. Therefore, 259PP individuals, who represent >25% of the general population, may be more susceptible to reduction of plasma tHcy concentrations by increasing the vitamin B(12) status