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© 2004 The American Society for Nutritional Sciences J. Nutr. 134:2985-2990, November 2004

Nutrient-Gene Interactions

Methionine Synthase Reductase 66A->G Polymorphism Is Associated with Increased Plasma Homocysteine Concentration When Combined with the Homozygous Methylenetetrahydrofolate Reductase 677C->T Variant1,2

Jaimie D. Vaughn, Lynn B. Bailey3, Karla P. Shelnutt, Kristina M. von-Castel Dunwoody, David R. Maneval, Steven R. Davis, Eoin P. Quinlivan, Jesse F. Gregory, III, Douglas W. Theriaque* and Gail P. A. Kauwell

Food Science and Human Nutrition Department and * General Clinical Research Center, University of Florida, Gainesville, FL 32611

3To whom correspondence should be addressed. E-mail: lbbailey{at}mail.ifas.ufl.edu.

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.

KEY WORDS: • folate • genetic polymorphisms • homocysteine • vitamin B-12




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