Transcobalamin C776G genotype modifies the association between vitamin B12 and homocysteine in older Hispanics

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.

Concept mapping One-Carbon Metabolism to model future ontologies for nutrient–gene–phenotype interactions

“…A few of the important pathways are visualized here. OCM is also important for providing cofactors and substrates for a multitude of subsequent reactions ranging from epigenetic methylation of genes to purine production folate, and riboflavin (Garrod et al 2010;Herbert and Zalusky 1962;Silla et al 2011;Yamada et al 2001;Yang et al 2008). MTR (Fig.…”

“…For example, homocysteine levels can be exacerbated by nutritionally related aberrations such as folic acid or vitamin B12 deficiency and lifestyle choices such as smoking (Garrod et al 2010;Nygård et al 1995). Homocysteine levels can also be mediated through nutritional therapy or physical activity (Yang et al 2008;Garrod et al 2010;Nygård et al 1995;Wernimont et al 2011). A combination of personalized nutritional therapy and lifestyle modifications could be suggested to individuals susceptible to hyperhomocysteinemia.…”

“…The malaria parasite requires OCM substrates as cofactors for enzymes essential for growth (Kronenberger et al 2014). The G allele may alter the structure of TCN2 so it has a lower affinity for B12, resulting in its more ready release (Afman et al 2002;Garrod et al 2010).…”

“…TCN2 efficiency directly affects the amount of vitamin B12 available for use by OCM (Garrod et al 2010;Silla et al 2011). This can be modeled easily within a CMAP because CMAP software is designed to flexibly incorporate all kinds of information.…”

“…Independent studies have already documented evidence that optimal vitamin intakes within a population vary due to single-nucleotide differences in genes within the OCM pathway (Bailey and Gregory 1999;Kelemen et al 2008;Stover and Garza 2002;Yang et al 2008;Zittan et al 2007). In addition to altered vitamin requirements, individuals with SNPs in genes encoding for enzymes residing along this pathway may also have increased susceptibility for comorbidity risk factors such as hyperhomocysteinemia (Garrod et al 2010) and diseases such as Alzheimer's type dementia (Cascalheira et al 2009) and cancer (Matakidou et al 2007;Vlastos et al 2009). …”