Hyperhomocysteinemia, a well-recognized cardiovascular risk factor, is frequent in
hemodialysis (HD) patients. A common polymorphism in the
5,10-methylenetetrahydrofolate reductase (MTHFR) gene, C-->T substitution at
nucleotide 677, is associated with
homocysteine (Hcy) level elevation. We examined whether three factors involved in the
methionine cycle could influence plasma Hcy concentrations in HD patients: MTHFR polymorphism;
vitamin B12, an essential cofactor; and
folate, the substrate. In a cross-sectional study, serum
vitamin B12,
folate, and plasma Hcy were measured and MTHFR genotyping was performed in 534 HD patients. Effects of MTHFR genotypes,
vitamin B12, and
folate on plasma Hcy levels were examined in 450 HD patients not administered
vitamin B12 or
folate. To examine the effect of
vitamin B12 on plasma Hcy concentrations, we compared plasma Hcy concentrations in HD patients with and without
vitamin B12 supplementation. To examine whether functional
vitamin B12 deficiency exists even in HD patients with normal
vitamin B12 concentrations, 15 HD patients (serum
vitamin B12 concentrations, 250 to 2,100 pg/mL) were treated with
vitamin B12 (
mecobalamin, 1.5 mg/d) for 8 weeks. Serum concentrations of
methylmalonic acid (MMA) and
vitamin B12 were measured. Hcy levels were higher and
folate levels were lower in patients with the TT and CT genotypes compared with patients with the CC genotype. Analysis of covariance to determine independent predictors of high Hcy levels identified low serum
vitamin B12 and
folate levels and high
albumin (Alb) levels in CC-genotype patients, low
folate levels and high Alb levels in CT-genotype patients, and low
folate levels in TT-genotype patients. Plasma Hcy levels were lower in CC- and CT-genotype patients with
vitamin B12 supplementation than in those without supplementation.
Vitamin B12 supplementation for 8 weeks significantly reduced MMA concentrations in HD patients with normal serum
vitamin B12 concentrations. These results indicate that MTHFR genotype influences the correlation of Hcy level with
vitamin B12 and
folate levels in HD patients. Functional
vitamin B12 deficiency may exist, even in HD patients with normal
vitamin B12 concentrations. The efficacy of
vitamin B12 and
folate supplementation on plasma Hcy levels may depend on MTHFR genotype.