Background:The standard screening test for vitamin B 12 deficiency, measurement of total plasma vitamin B 12 , has limitations of sensitivity and specificity. Plasma vitamin B 12 bound to transcobalamin (holoTC) is the fraction of total vitamin B 12 available for tissue uptake and therefore has been proposed as a potentially useful alternative indicator of vitamin B 12 status. Methods: We compared the diagnostic accuracy of total vitamin B 12 , holoTC, and a combination of both measures to screen for metabolic vitamin B 12 deficiency in an elderly cohort (age >60 years). Plasma methylmalonic acid and homocysteine were used as indicators of vitamin B 12 deficiency. Results: Low total vitamin B 12 (<148 pmol/L) and low holoTC (<35 pmol/L) were observed in 6.5% and 8.0%, and increased methylmalonic acid (>350 nmol/L) and homocysteine (>13 mol/L) were observed in 12.1% and 17.0% of the study participants. In multiple regression models, holoTC explained 5%-6% more of the observed variance in methylmalonic acid and homocysteine than did total vitamin B 12 (P <0.004). ROC curve analysis indicated that total vitamin B 12 and holoTC were essentially equivalent in their ability to discriminate persons with and without vitamin B 12 deficiency. Individuals

A common polymorphism (775G>C) in the vitamin B12 transport protein, transcobalamin II (TCII), has been identified in which proline replaces arginine at codon 259. We determined the influence of TCII genotype on indices of B12 status, including total serum B12, the amount of B12 bound to TCII (holoTCII), methylmalonic acid, and homocysteine, in 128 healthy older adults (ages 40-88 years). Mean total B12 and homocysteine concentrations were not significantly different among the 3 genotypes. Mean holoTCII concentration was significantly higher in those subjects homozygous for the proline form of TCII (PP) compared with those homozygous for the arginine form (RR) and heterozygotes (PR) (P < .006). In addition, mean methylmalonic acid concentrations were significantly lower in the PP and PR groups compared with the RR group (P < .02). The PP genotype may be more efficient in delivering B12 to tissues, resulting in enhanced B12 functional status. TCII genotype may thus influence susceptibility to B12 deficiency. IntroductionThe serum protein, transcobalamin II (TCII), transports vitamin B12 (B12) from the ileum to the tissues. The B12-TCII complex (holoTCII) is then taken up into cells by receptor-mediated endocytosis. In the 1970s and 1980s, 2 research groups independently identified distinct isopeptide forms of TCII by polyacrylamide gel electrophoresis 1,2 and isoelectric focusing. 3 More recently, DNA sequencing has revealed that the isopeptide forms of TCII are the result of single nucleotide polymorphisms. [4][5][6] The most common polymorphism in white populations is a G-to-C substitution at base position 775 (775GϾC), which results in the replacement of proline with arginine at codon 259. Recently, the potential influence of the 775GϾC polymorphism on indices of vitamin B12 status has been investigated. Persons homozygous for the proline form of the protein (PP) tend to have higher holoTCII but similar total serum B12 concentrations compared with those homozygous for the arginine form (RR). [7][8][9][10][11] One group has found that homocysteine, a functional indicator of B12 status, is higher in heterozygous persons (PR) than in PP and RR persons, 8,11 but this finding was not confirmed. 9,10 Notably, the relationship between TCII genotype and methylmalonic acid, potentially a more specific indicator of B12 status than homocysteine, has not been reported. Therefore, we assessed the relationship between 775GϾC TCII genotype and methylmalonic acid and between total B12, holoTCII, and homocysteine in a cohort of healthy older adults. Study design SubjectsThe study sample consisted of 108 men and 20 women (mean age, 67 years; range, 40-88 years). Subjects are current participants in the Longitudinal Aging Study, initiated in 1969 and continuing through the present at the University of Missouri-Columbia. 12 The study population consisted primarily of University of Missouri faculty and staff who were physically active and in apparent good health, with no evidence of decreased intrinsic factor secretion or gastroi...

Low vitamin B-12 is associated with more pronounced metabolic evidence of vitamin B-12 deficiency when folate is elevated than when folate is not elevated. These data should be considered when assessing the potential costs, risks, and benefits of folic acid and vitamin B-12 fortification programs.