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

Abstract

Two polymorphic variants in the gene coding for transcobalamin II (TCN2), TCN2 776C- > G and TCN2 67A- > G, may alter serum holotranscobalamin (holoTC), which in turn may affect cellular uptake of cobalamin (Cbl) and thereby Cbl status indicators. We studied the effects of TCN2 776C- > G and TCN2 67A- > G on blood concentrations of holoTC, Cbl, methylmalonic acid (MMA), and total homocysteine (tHcy) in 2411 individuals (50-64 y) that had been selected on the basis of these TCN2 genotypes from 10601 Norwegian inhabitants. The serum holoTC concentration was lower in TCN2 67AG (55 ± 0.75 pmol/L) and 67GG (48 ± 2.14 pmol/L) than in 67AA (62 ± 0.67 pmol/L) (P < 0.001) but did not differ among TCN2 776C- > G genotypes. The polymorphisms interacted as serum holoTC determinants (P = 0.001) and the presence of TCN2 67AG and GG in strata of 776CC and CG, but not 776GG, increased the risk of having serum holoTC < 45.6 pmol/L [tertile 1 vs. tertiles 2 and 3: OR = 2.5 (95% CI 1.8-3.5) for 67AG; OR = 5.7 (95% CI 3.5-9.1) for 67GG in 776CC; OR = 2.1 (95% CI 1.6-2.9) for 67AG; and OR = 4.5 (95% CI 2.4-8.2) for 67GG in 776CG; all P < 0.001]. Plasma MMA, tHcy, and Cbl were not affected by either polymorphism. In summary, serum holoTC, but not plasma Cbl, MMA, or tHcy, varied according to TCN2 67A- > G genotypes. It remains to be determined whether this polymorphic effect on serum holoTC alters its diagnostic utility as Cbl status indicator.

Three family members with elevated plasma cobalamin, transcobalamin and soluble transcobalamin receptor (sCD320)

“…The p.P259R variant has been reported to have no effect [ 25 ] or to be related to only moderately elevated levels of TC [ 26 -28 ], levels that are much lower than observed in our patients. Thus, any genetic cause was unlikely to explain the observed elevation in TC.…”

Genetic polymorphisms modulate the folate metabolism of Brazilian individuals with Down syndrome

“…This suggests [36][37][38] in addition to increased MMA [39] and Hcy concentrations [37,40]. Previous studies, however, did not find an association between this polymorphism and either holotranscolbalamin [41] or Hcy [38,42]. Furthermore, an increase in Hcy concentration was shown to be associated with the heterozygous TCN2 776 CG genotype when compared to the homozygous genotypes [36].…”

Cellular uptake of cobalamin: Transcobalamin and the TCblR/CD320 receptor

“…Even though direct proof is lacking, megalin is highly expressed in embryonic tissue and is a likely candidate receptor for TC-Cbl during fetal development. While there is no clear consensus on the association of maternal low Cbl status and birth defects, most studies have shown some albeit, weak correlation with low Cbl status and elevated matabolites such as HCY and MMA (52-55). A stronger correlation was observed with a decrease in the level of maternal holo TC with increased risk for birth defects.…”