The ratio of holotranscobalamin to total B12: associations with transcobalamin genotype, methylmalonic acid, and homocysteine

Abstract

A common polymorphism, C776G, in the plasma B12 transport protein, transcobalamin (TC), encodes for either proline or arginine at codon 259. In a previous study, we demonstrated that individuals homozygous for the arginine isoform (RR) had a lower percentage of total plasma B12 bound to TC (holoTC/total B12 ratio) than those homozygous for the proline isoform (PP). In the present study, we investigated TC genotype and the potential significance of the holoTC/total B12 ratio in a cohort of elderly Latinos (N=833, age 60-93y) participating in the Sacramento Area Latino Study on Aging (SALSA). The distribution of TC genotypes was 40.6% homozygous for the proline isoform (PP) and 11.6% homozygous for the arginine isoform (RR). Consistent with our previous study, the RR genotype was associated with a lower median holoTC/total B12 ratio than the PP genotype (0.27 vs. 0.23, p=0.002). In multiple regression analyses controlling for age, sex, creatinine, and folate, the holoTC/total B12 ratio was inversely associated with the functional indicators of B12 status, methylmalonic acid (p=0.001) and homocysteine (p<0.001). These data indicate that for a given level of total B12, the percentage of the total on TC is a strong determinant of functional B12 status, and TC genotype is an important determinant of that percentage. Further studies are needed to determine if TC genotype and the holoTC/total B12 ratio contribute to the increased risk of vascular disease and dementia associated with hyperhomocysteinemia. NIH AG12975; USDA 00-35200-9073