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

Abstract

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 B 12 from blood into cells. This study was undertaken to assess the relationship between the transcobalamin P259R (TCN2 776C4G) 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 776C4G genotypes were determined using a TaqMan 5 0 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 ¼ 0.01; P adjusted ¼ 0.03) and 776GG genotypes (P unadjusted ¼ 0.015; P adjusted ¼ 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 ¼ 0.015; P adjusted ¼ 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 776C4G genotype and tHcy concentrations. Thus, the TCN2 776C4G polymorphism may contribute to the risk of pathologies associated with a low B 12 , and high tHcy phenotype.

Transcobalamin Polymorphism 67A->G, but Not 776C->G, Affects Serum Holotranscobalamin in a Cohort of Healthy Middle-Aged Men and Women

“…G (rs1801198; p.Pro259Arg) has been extensively investigated in relation to transport of Cbl in plasma and Cbl delivery into the cell. However, published data on the influence of this polymorphism on serum holoTC and associations with plasma concentrations of Cbl, MMA, or tHcy are conflicting (11)(12)(13)(14)(15)(16)(17)(18)(19)(20). Moreover, knowledge of the associations between indicators of Cbl status and TCN2 67A-.…”

Transcobalamin 776C→G polymorphism is associated with peripheral neuropathy in elderly individuals with high folate intake

“…Thus, total homocysteine and methylmalonic acid in plasma serve as functional biomarkers for vitamin B-12 status in tissues. The GG genotype of the 776C/G polymorphism of TCN2 is associated with a higher concentration of homocysteine in individuals with lower plasma vitamin B-12 (6). However, the G allele has also been reported to be associated with lower homocysteine under low vitamin B-12 status (7).…”

“…We did not observe a relation between the TCN2 polymorphism and plasma concentration of total homocysteine. There have been contradictory reports of higher homocysteine in individuals with GG genotypes (6,33) as well as a lack of a genotype effect (4,34).…”

An Analysis of Transcobalamin II Gene Polymorphisms and Serum Levels of Homocysteine, Folate and Vitamin B₁₂ in Chinese Patients with Crohn's Disease

“…Subsequently, this alteration may affect the binding affinity of vitamin B 12 to TCN II protein and the recognition of holotranscobalamin (holo-TC) by the receptors responsible for its endocytosis [21,22] . Another common functional locus of TCN2 (rs9606756) is positioned at the exon 2, whose mutation 12 .…”