The transcobalamin (TCN2) 776C>G polymorphism affects homocysteine concentrations among subjects with low vitamin B(12) status.
OBJECTIVE
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 776C>G) polymorphism and both serum vitamin B(12) and total Hcy (tHcy) levels.


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 B(12), and high tHcy phenotype.
Stanisławska-Sachadyn
A
A
Department of Pharmacology and Center for Pharmacogenetics, University of Pennsylvania School of Medicine, Philadelphia, PA 19104-6084, USA.
Woodside
J V
JV
Sayers
C M
CM
Yarnell
J W
JW
Young
I S
IS
Evans
A E
AE
Mitchell
L E
LE
Whitehead
A S
AS
D000328:Adult; D005838:Genotype; D006710:Homocysteine / Q000097:blood / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D007494:Ireland; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D014155:Transcobalamins / Q000235:genetics*; D014805:Vitamin B 12 / Q000097:blood / Q000235:genetics*; D014804:Vitamin B Deficiency / Q000097:blood / Q000235:genetics*
D014155:Transcobalamins; D006710:Homocysteine; D014805:Vitamin B 12