The transcobalamin (TCN2) 776C>G polymorphism affects homocysteine concentrations among subjects with low vitamin B12 status

Background/Objectives: Methionine synthase catalyzes the conversion of 5-methyltetrahydrofolate to tetrahydrofolate and homocysteine (Hcy) to methionine using vitamin B12 as a cofactor. Transcobalamin is the main transporter of vitamin B12 from blood into cells. This study was undertaken to assess the relationship between the transcobalamin P259R (TCN2 776C>G) polymorphism and both serum vitamin B12 and total Hcy (tHcy) levels. Subjects/Methods: The population comprised 613 men from Northern Ireland, aged 30–49 years, for whom tHcy, serum vitamin B12 and serum folate concentrations were available. TCN2 776C>G genotypes were determined using a TaqMan 5′ nuclease Real-Time PCR assay. Standard statistical tests of association were applied to assess the relationships between the polymorphism and phenotypic variables. Results: The TCN2 776CC homozygous genotype was associated with lower serum vitamin B12 concentrations compared with the 776CG (Punadjusted=0.01; Padjusted=0.03) and 776GG genotypes (Punadjusted=0.015; Padjusted=0.045). Among individuals with vitamin B12 concentrations in the lower half of the distribution, tHcy concentrations were higher in TCN2 776GG homozygotes than in individuals with the other genotypes (Punadjusted=0.015; Padjusted=0.06). Conclusions: These data suggest that, relative to transcobalamin with arginine at position 259 (776G), transcobalamin with proline at this position (776C) is either more efficient at vitamin B12 transport from blood to tissues or has higher affinity for vitamin B12. Furthermore, vitamin B12 status influences the relationship between TCN2 776C>G genotype and tHcy concentrations. Thus, the TCN2 776C>G polymorphism may contribute to the risk of pathologies associated with a low B12, and high tHcy phenotype.