title: Methionine synthase reductase 66A->G polymorphism is associated with increased plasma homocysteine concentration when combined with the homozygous methylenetetrahydrofolate reductase 677C->T variant.
abstract: Methylenetetrahydrofolate reductase (MTHFR) and methionine synthase reductase (MTRR) are important for homocysteine remethylation. This study was designed to determine the influence of genetic variants (MTHFR 677C-->T, MTHFR 1298A-->C, and MTRR 66A-->G), folate, and vitamin B-12 status on plasma homocysteine in women (20-30 y; n = 362). Plasma homocysteine was inversely (P < 0.0001) associated with serum folate and plasma vitamin B-12 regardless of genotype. Plasma homocysteine was higher (P < 0.05) for women with the MTHFR 677 TT/1298 AA genotype combination compared with the CC/AA, CC/AC, and CT/AA genotypes. Women with the MTHFR 677 TT/MTRR 66 AG genotype had higher (P < 0.05) plasma homocysteine than all other genotype combinations except the TT/AA and TT/GG genotypes. There were 5.4-, 4.3-, and 3.8-fold increases (P < 0.001) in risk for plasma homocysteine in the top 5, 10, and 20%, respectively, of the homocysteine distribution for subjects with the MTHFR 677 TT compared with the CC and CT genotypes. Predicted plasma homocysteine was inversely associated with serum folate (P = 0.003) and plasma vitamin B-12 (P = 0.002), with the degree of correlation dependent on MTHFR 677C-->T genotype. These data suggest that coexistence of the MTHFR 677 TT genotype with the MTRR 66A-->G polymorphism may exacerbate the effect of the MTHFR variant alone. The potential negative effect of combined polymorphisms of the MTHFR and MTRR genes on plasma homocysteine in at-risk population groups with low folate and/or vitamin B-12 status, such as women of reproductive potential, deserves further investigation.
authors.affiliation: Food Science and Human Nutrition Department, University of Florida, Gainesville, FL 32611, USA.
authors.forename: Jaimie D
authors.initials: JD
authors.lastname: Vaughn
authors.forename: Lynn B
authors.initials: LB
authors.lastname: Bailey
authors.forename: Karla P
authors.initials: KP
authors.lastname: Shelnutt
authors.forename: Kristina M von-Castel
authors.initials: KM
authors.lastname: Dunwoody
authors.forename: David R
authors.initials: DR
authors.lastname: Maneval
authors.forename: Steven R
authors.initials: SR
authors.lastname: Davis
authors.forename: Eoin P
authors.initials: EP
authors.lastname: Quinlivan
authors.forename: Jesse F
authors.initials: JF
authors.lastname: Gregory
authors.forename: Douglas W
authors.initials: DW
authors.lastname: Theriaque
authors.forename: Gail P A
authors.initials: GP
authors.lastname: Kauwell
mesh_terms: D000328:Adult; D019587:Dietary Supplements; D005260:Female; D005287:Ferredoxin-NADP Reductase / Q000235:genetics*; D005492:Folic Acid / Q000008:administration & dosage / Q000097:blood; D005787:Gene Frequency; D005838:Genotype; D006710:Homocysteine / Q000008:administration & dosage / Q000097:blood*; D006720:Homozygote; D006801:Humans; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics*; D011110:Polymorphism, Genetic; D014805:Vitamin B 12 / Q000008:administration & dosage / Q000097:blood
chemical_list: D006710:Homocysteine; D005492:Folic Acid; C111241:methionine synthase reductase; D005287:Ferredoxin-NADP Reductase; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D014805:Vitamin B 12