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LETTER TO THE EDITOR |
G polymorphism is influenced by folate in the absence of supplementation and fortified diet
Inserm U-724
Cellular and Molecular Pathology in Nutrition
Faculté de Médecine
University Henry Poincaré of Nancy
BP 184 54500 Vandoeuvre lès
Nancy, France
E-mail:jl.gueant{at}chu-nancy.fr
Dear Sir:
von Castel-Dunwoody et al (1, 2) recently reported that vitamin B-12 modulates the blood concentration of total homocysteine (tHcy) in a group of 359 nonpregnant young women who were previously characterized for folate and genetic determinants of tHcy. In our opinion, these interesting data may be reevaluated considering the folic acid fortification of grain products that was initiated in the United States (3). The high serum concentration and high dietary intake of folate may explain, at least in part, the significant association between tHcy and vitamin B-12. Quinlivan et al (4) showed that the usual dependency of homocysteine on folate diminishes and the vitamin B-12 concentration becomes the main determinant of tHcy in subjects who receive supplements with increasing doses of folic acid. Similarly, von Castel-Dunwoody et al (2) found a weak association between tHcy and folate but a stronger association between tHcy and vitamin B-12.
We evaluated the influence of folate on the association between tHcy and vitamin B-12 in a group of 114 adults from Western Europe who neither received supplements nor ate folate-enriched food. These subjects were studied in 2 previously published reports (5, 6). Compared with the group of von Castel-Dunwoody et al (1), these subjects had a higher plasma tHcy concentration (10.9 ± 3.4 compared with 6.3 ± 1.3 µmol/L), a much lower folate concentration (12.9 ± 4.6 compared with 50.2 ± 21.1 nmol/L), and no association between tHcy and vitamin B-12 (r = –0.093, P = 0.3272), despite a significant association between tHcy and folate (r = –0.217, P = 0.0253). When we stratified the association between tHcy and vitamin B-12 by quartiles of folate, it became significant only for the upper quartile (folate >15.0 nmol/L; r = –0.395, P = 0.0339). Similarly, we observed an association between tHcy and holo-transcobalamin only when folate concentrations were in the upper quartile (r = –0.394, P = 0.0379). In addition, the holo-transcobalamin concentration was highest in this upper quartile of folate (P < 0.0176), whereas no significant interaction was reported between quartiles of folate and either vitamin B-12 (P = 0.4644) or apo-transcobalamin (P = 0.7760). Therefore, these data suggest that the influence of folate on the association between tHcy and vitamin B-12 can be observed not only in subjects who receive either a fortified diet or vitamin supplements but also in those who have a relatively high dietary intake of folate.
A second interesting finding of von Castel-Dunwoody et al (1) was that the transcobalamin 776C
G polymorphism (P259R) negatively affected serum holo-transcobalamin, as previously shown (7). In their study, the 259RR variants had a holo-transcobalamin concentration that was 1.18-fold lower than those of the 259PP variant, with a significant mean difference of 13 pmol/L (1). We reported a 1.16-fold lower holo-transcobalamin concentration in the 259RR variants than in the 259PP variants, but this small difference was not statistically significant (P = 0.2260), possibly as the result of the limited size of our sample population. In contrast, there was a clear-cut difference in apo-transcobalamin concentration, with a 1.59-fold lower concentration in the 259RR variants (
: 250 pmol/L; range: 219–308 pmol/L) than in the 259PP and 259PR variants (: 387 pmol/L; range: 317–463 pmol/L; P < 0.0001), as previously reported (5). The greater influence of this polymorphism on apo-transcobalamin concentrations, as opposed to holo-transcobalamin, suggests a difference between the variants in the vitamin B-12 binding affinity or blood half-life. However, when stratifying the analysis by quartiles of vitamin B-12 concentrations, the holo-transcobalamin concentration between the different genotypes was not influenced by vitamin B-12. Our group was the first to report that the P259R substitution previously observed in Caco-2 cells and HT 29 cells was a polymorphism and to show its association with transcobalamin concentration in cells and in blood (5, 8). We studied the molecular mechanisms underlying the difference in the expression level of the variants. We found that the RR variant was associated with a lower level of transcripts than were the PR and PP variants and that the isoelectric point of the native and recombinant RR variant shifted under both nondenaturing and denaturating conditions, which suggested conformational changes. However, in contrast with the references cited (7, 9) in the article by von Castel-Dunwoody et al (1), there is, to our knowledge, no direct evidence to support the hypothesis that the 2 transcobalamin variants have different vitamin B-12 binding affinities and different abilities to deliver vitamin B-12 to cells. In our population (5, 6), we found that tHcy was significantly higher in the 259PR heterozygous carriers (median: 11.5 µmol/L; interquartile range: 9.6–14.8 µmol/L) than in the 259PP and 259RR carriers (medians: 9.8 and 9.9 pmol/L, respectively; interquartile ranges: 7.3–11.5 and 8.4–11.7 pmol/L, respectively; P = 0.0015). When stratifying the univariate analysis by quartiles of plasma B-12, we found no influence of vitamin B-12 on this association.
Because we showed that folate concentrations may influence the association between tHcy and holo-transcobalamin, we aimed to investigate its influence on the association between tHcy and the transcobalamin 776CG polymorphism. Surprisingly, we found that the polymorphism remained a significant determinant of tHcy only in the subjects who had a folate concentration in the lowest quartile. In this subset of the population, tHcy was highest in heterozygous variants (tHcy in the 259PR variants: median: 12.2 pmol/L; interquartile range: 11.8–15.8; tHcy in the 259PP and 259RR variants: median: 10.5 pmol/L; interquartile range: 6.5–12.4 pmol/L; P = 0.0009). The association between the transcobalamin polymorphism and tHcy was not related to transcobalamin concentrations, because the lowest concentrations were recorded in 259RR carriers. We previously suggested that the transcobalamin heterozygous genotype may exhibit a lower affinity to the receptor than do the homozygous genotypes, but this needs to be confirmed by direct binding experiments, because the functional properties of the transcobalamin receptor are still a matter of debate (10).
The high folate concentration reported for the population studied by von Castel-Dunwoody et al (1) may therefore explain, at least in part, why tHcy was not influenced by the transcobalamin polymorphism, despite its association with holo-transcobalamin. Indeed, the association between the transcobalamin 776CG polymorphism and tHcy that was reported in our subjects seemed not to depend on the concentration of holo-transcobalamin. Rather, it was influenced by low serum folate concentrations, at least in a population that was exempted from a folate-fortified diet or folate supplementation.
ACKNOWLEDGMENTS
The authors had no conflicts of interest.
REFERENCES
G polymorphism negatively affects vitamin B-12 metabolism. Am J Clin Nutr 2005;81:1436–41.G polymorphism is associated with increased plasma homocysteine concentration when combined with the homozygous methylenetetrahydrofolate reductase 677CT variant. J Nutr 2004;134:2985–90.C polymorphism and indices of vitamin B12 status in healthy older adults. Blood 2002;100:718 –20.
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