title: 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 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.
authors.affiliation: Division of Blood Transfusion and Mathematical Informative Science, Yamanashi Medical University, Tago Clinic, Yamanashi, Japan. highway@athena.ocn.ne.jp
authors.forename: Takamichi
authors.initials: T
authors.lastname: Nakamura
authors.forename: Katsu
authors.initials: K
authors.lastname: Saionji
authors.forename: Yoshimitsu
authors.initials: Y
authors.lastname: Hiejima
authors.forename: Hideo
authors.initials: H
authors.lastname: Hirayama
authors.forename: Kiichiro
authors.initials: K
authors.lastname: Tago
authors.forename: Hajime
authors.initials: H
authors.lastname: Takano
authors.forename: Munemasa
authors.initials: M
authors.lastname: Tajiri
authors.forename: Katsuji
authors.initials: K
authors.lastname: Hayashi
authors.forename: Masaki
authors.initials: M
authors.lastname: Kawabata
authors.forename: Makiko
authors.initials: M
authors.lastname: Funamizu
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Makita
authors.forename: Akira
authors.initials: A
authors.lastname: Hata
mesh_terms: D003430:Cross-Sectional Studies; D019587:Dietary Supplements; D005260:Female; D005492:Folic Acid / Q000097:blood / Q000502:physiology*; D005494:Folic Acid Deficiency / Q000378:metabolism; D005838:Genotype; D006710:Homocysteine / Q000097:blood / Q000172:deficiency; D006801:Humans; D020138:Hyperhomocysteinemia / Q000209:etiology; D007676:Kidney Failure, Chronic / Q000150:complications / Q000628:therapy; D008297:Male; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D008764:Methylmalonic Acid / Q000097:blood; D008875:Middle Aged; D000587:Oxidoreductases Acting on CH-NH Group Donors / Q000235:genetics*; D011110:Polymorphism, Genetic / Q000235:genetics; D006435:Renal Dialysis / Q000379:methods; D014805:Vitamin B 12 / Q000097:blood / Q000502:physiology*; D014806:Vitamin B 12 Deficiency / Q000378:metabolism
chemical_list: D006710:Homocysteine; D008764:Methylmalonic Acid; D005492:Folic Acid; D000587:Oxidoreductases Acting on CH-NH Group Donors; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D014805:Vitamin B 12