Methylenetetrahydrofolate reductase genotype, vitamin B12, and folate influence plasma homocysteine in hemodialysis patients.

Abstract 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 B 12 , an essential cofactor; and folate, the substrate. In a cross-sectional study, serum vitamin B 12 , folate, and plasma Hcy were measured and MTHFR genotyping was performed in 534 HD patients. Effects of MTHFR genotypes, vitamin B 12 , and folate on plasma Hcy levels were examined in 450 HD patients not administered vitamin B 12 or folate. To examine the effect of vitamin B 12 on plasma Hcy concentrations, we compared plasma Hcy concentrations in HD patients with and without vitamin B 12 supplementation. To examine whether functional vitamin B 12 deficiency exists even in HD patients with normal vitamin B 12 concentrations, 15 HD patients (serum vitamin B 12 concentrations, 250 to 2,100 pg/mL) were treated with vitamin B 12 (mecobalamin, 1.5 mg/d) for 8 weeks. Serum concentrations of methylmalonic acid (MMA) and vitamin B 12 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 B 12 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 B 12 supplementation than in those without supplementation. Vitamin B 12 supplementation for 8 weeks significantly reduced MMA concentrations in HD patients with normal serum vitamin B 12 concentrations. These results indicate that MTHFR genotype influences the correlation of Hcy level with vitamin B 12 and folate levels in HD patients. Functional vitamin B 12 deficiency may exist, even in HD patients with normal vitamin B 12 concentrations. The efficacy of vitamin B 12 and folate supplementation on plasma Hcy levels may depend on MTHFR genotype. © 2002 by the National Kidney Foundation, Inc.