ARS | Publication request: Transcobalamin C776G genotype modifies the association between vitamin B12 and homocysteine in older hispanics

Submitted to: European Journal of Clinical Nutrition
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: December 27, 2009
Publication Date: March 20, 2010
Repository URL: http://www.nature.com/ejcn/journal/v64/n5/pdf/ejcn201020a.pdf
Citation: Garrod, M.G., Allen, L.H., Haan, M.N., Green, R., Miller, J.W. 2010. Transcobalamin C776G genotype modifies the association between vitamin B12 and homocysteine in older hispanics. European Journal of Clinical Nutrition. 64:503-509, 2010.

Interpretive Summary: Vitamin B12 is transported in the plasma and into cells bound to the protein transcobalamin (TC). The gene for TC has several single nucleotide polymorphisms (SNPs). One of these, which is relatively common, has a cytosine-to-guanosine substitution at base position 776 of the genomic DNA sequence (776C>G). This causes arginine to substitute for proline in the TC protein but it is not known if this affects the structure and function of TC, for example its delivery of vitamin B12 to tissues. This question was investigated in plasma samples from 554 elderly Latinos, age 60-93 y, in the Sacramento Area Latino Study on Aging (SALSA). The homozygous reference TC genotype (776CC) was present in 41.3% of the group, and the homozygous variant (776GG) in 11.6%. The homozygous genotypes did not differ in total B12, holoTC, methylmalonic acid or homocysteine, but the toloTC/total B12 ratio was lower in the 776GG group. Homocysteine concentrations were higher, and more exceeded acceptable values, in the 776CC subjects with low plasma B12 (<156 pmol/L) or TC (<35 pmol/L) than in those with the G allele (776CG and 776GG combined). This study reveals that the association between plasma B12 and homocysteine concentrations is modified by TC genotype. Whether there are other functional manifestations of vitamin B12 deficiency in persons with this genotype remains to be determined.

Technical Abstract: Background: A common polymorphism, C776G, in the plasma B12 transport protein transcobalamin (TC), encodes for either proline or arginine at codon 259. This polymorphism may affect the affinity of TC for B12 and subsequent delivery of B12 to tissues. Methods: TC genotype and its associations with indicators of B12 status, including total B12, holotranscobalamin (holoTC), methylmalonic acid, and homocysteine, were evaluated in a cohort of elderly Latinos (N=554, age 60-93y) from the Sacramento Area Latino Study on Aging (SALSA). Results: The distribution of TC genotypes was 41.3% homozygous reference (776CC) and 11.6% homozygous variant (776GG). No differences between the homozygous genotypes were observed in total B12, holoTC, , methylmalonic acid or homocysteine. The holoTC/total B12 ratio was lower in the 776GG group compared with the 776CC group (p=0.04). Significant interactions of TC genotype with total B12 (p=0.04) and with holoTC (p=0.03) were observed such that mean homocysteine concentrations and the odds ratios for hyperhomocysteinemia (>13 µmol/L) were higher in the 776CC subjects compared with all carriers of the G allele (776CG and 776GG combined) when total B12 (<156 pmol/L) or holoTC (<35 pmol/L) were low. Conclusions: This population of older Latinos has a lower prevalence of the TC 776GG variant than reported for Caucasian populations. The association between vitamin B12 and homocysteine concentrations is modified by TC 776 genotype. It remains to be determined if the TC C776G polymorphism has a significant effect on the hematological and neurological manifestations of B12 deficiency or on vascular and other morbidities associated with hyperhomocysteinemia.