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 B-12 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 B-12 and total Hcy (tHcy) levels. Subjects/Methods: The population comprised 613 men from Northern Ireland, aged 30-49 years, for whom tHcy, serum vitamin B-12 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 B-12 concentrations compared with the 776CG (P-unadjusted = 0.01; P-adjusted = 0.03) and 776GG genotypes (P-unadjusted = 0.015; P-adjusted = 0.045). Among individuals with vitamin B-12 concentrations in the lower half of the distribution, tHcy concentrations were higher in TCN2 776GG homozygotes than in individuals with the other genotypes (P-unadjusted = 0.015; P-adjusted = 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 B-12 transport from blood to tissues or has higher affinity for vitamin B-12. Furthermore, vitamin B-12 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. European Journal of Clinical Nutrition (2010) 64, 1338-1343; doi: 10.1038/ejcn.2010.157; published online 1 September 2010