Transcobalamin 776C→G polymorphism is associated with peripheral neuropathy in elderly individuals with high folate intake

Abstract

Background: The 776C/G polymorphism of the vitamin B-12 transport protein transcobalamin gene (TCN2) (rs1801198; Pro259Arg) is associated with a lower holotranscobalamin concentration in plasma. This effect may reduce the availability of vitamin B-12 to tissues even when vitamin B-12 intake is adequate. Clinical outcomes associated with vitamin B-12 insufficiency could potentially be worsened by high folate intake. Objective: We determined the association of the TCN2 776C/G polymorphism and folate intake with peripheral neuropathy in elders with normal plasma concentrations of vitamin B-12. Design: Participants in this cross-sectional study (n = 171) were from a cohort of community-based, home-bound elderly individuals aged $60 y who underwent an evaluation by physicians including an assessment for peripheral neuropathy. Participants were administered food-frequency and general health status questionnaires, anthropometric measurements were taken, and a fasting blood sample from each subject was collected. Results: Odds of neuropathy were 3-fold higher for GG genotypes than for CC genotypes (OR: 3.33; 95% CI: 1.15, 9.64). When folate intake was .2 times the Recommended Dietary Allowance (800 mg), GG genotypes had 6.9-fold higher odds of neuropathy than CC genotypes (OR: 6.9; 95% CI: 1.31, 36.36). There was no difference between the genotypes in the odds of peripheral neuropathy when folate intake was #800 mg (OR: 1.5; 95% CI: 0.18, 12.33). Conclusion: The TCN2 776C/G polymorphism is associated with increased odds of peripheral neuropathy in the elderly, even with a normal vitamin B-12 status, especially if their folate intake is .2 times the Recommended Dietary Allowance.Am J Clin Nutr 2016;104:1665-70.

Do the benefits of folic acid fortification outweigh the risk of masking vitamin B12deficiency?

“…Similarly, in elderly people with the transcobalamin 776GG genotype, which affects uptake of vitamin B 12, the risk of peripheral neuropathy was three times that of those with the CC genotype; the risk associated with the GG genotype was doubled in those whose folate was twice the recommended allowance (odds ratio 6.9 versus 3.3) 26. After fortification was introduced in the US the prevalence of low vitamin B 12 levels increased even in the absence of macrocytosis or anaemia 27…”

Association of TCN2 rs1801198 c.776G>C polymorphism with markers of one-carbon metabolism and related diseases: a systematic review and meta-analysis of genetic association studies

“…Thus, with only 4 studies included, the meta-analysis on the association between rs1801198 and MMA lacked statistical power. The Funnel plot showed risk of bias that was related to studies that were reported by Sawaengsri et al (36) and McCaddon et al (30) in relation to the vitamin B-12 meta-analysis (Supplemental Figure 1). Table S1, Online Supporting Material Supplemental Table 1.…”

“…When all studies were included in the meta-analysis, the homocysteine concentration was not significantly higher in subjects with the GG genotype than in those with a CC genotype with an SMD 6 SE of 0.112 6 0.058 [95% CI: 20.020, 0.240; P = 0.09 (HKSJ)] and an I 2 of 36.23% (95% CI: 0.00%, 68.66%; P = 0.11) ( Figure 2C, Table 5). The funnel plot showed risk of bias that was related to the study by Sawaengsri et al (36) (Supplemental Figure 1). When the metaanalysis included only the 8 studies in European-ancestry subjects (14,(26)(27)(28)(29)(33)(34)(35), homocysteine was significantly higher in subjects who harbored the GG genotype than in those with the CC genotype with an SMD 6 SE of 0.070 6 0.021 [95% CI: 0.020, 0.120; P = 0.01 (HKSJ)] and no heterogeneity (I 2 = 0.00%; 95% CI: 0.00%, 49.59%; P = 0.73) (Supplemental Figure 1, Figure 2C, Table 5).…”

“…Eleven studies in 13,139 subjects assessed the concentration of homocysteine according to rs1801198 (14,(26)(27)(28)(29)(31)(32)(33)(34)(35)(36). When all studies were included in the meta-analysis, the homocysteine concentration was not significantly higher in subjects with the GG genotype than in those with a CC genotype with an SMD 6 SE of 0.112 6 0.058 [95% CI: 20.020, 0.240; P = 0.09 (HKSJ)] and an I 2 of 36.23% (95% CI: 0.00%, 68.66%; P = 0.11) ( Figure 2C, Table 5).…”

Peripheral neuropathy risk and a transcobalamin polymorphism: connecting the dots between excessive folate intake and disease susceptibility

“…Further adding to the complexity of gene-nutrient interactions and their effects on disease susceptibility and severity are the constellations of interactive polymorphisms in one-carbon metabolism, together with substrate and cofactor availability, all of which may affect resultant phenotypes (1). The article by Sawaengsri et al (2) in this issue of the Journal, which reports that the common 776C/G polymorphism in the transcobalamin (TCN2) vitamin B-12 transporter gene is associated with peripheral neuropathy in elderly individuals with high folate intakes, informs on the currently vexed question of folate fortification and supplement use.…”