Methylenetetrahydrofolate reductase (MTHFR) c677t gene variant modulates the homocysteine folate correlation in a mild folate-deficient population

Background: A large body of evidence links plasma concentrations of homocysteine and cardiovascular disease. Several genetic and environmental variables may modulate such relationship. We investigated the influence of methylenetetrahydrofolate reductase (MTHFR) gene variants C677T, A1298C, and T1317C on homocysteine, folate, and cobalamin concentrations in a sample of individuals from a mild folate deficiency population to better clarify the complex interactions existing among these variables. Methods: In the present study, 209 individuals belonging to an admixed urban population characterized by mild folate deficiency were investigated. MTHFR gene variants C677T, A1298C, and T1317C were genotyped and homocysteine-, folate-, and cobalamin-determined for each individual. Results: Univariate analyses showed a significant association between the C677T variant with homocysteine (P < 0.001) and cobalamin (P = 0.005) as well as a significant relationship between the T allele and serum folate concentrations (P < 0.05). The TT genotype of the C677T polymorphism remained significantly associated with log-transformed homocysteine even after adjustment for age, sex, smoking status, ethnicity, folate, and cobalamin concentrations (P < 0.01). Both univariate and multivariate analysis have failed to show any effect of the A1298C and T1317C genetic variants in homocysteine concentrations in this population. Finally, a significant interaction between folate and C677T polymorphism in the determination of homocysteine was also disclosed (P< 0.005). Conclusions: Taken together, these results demonstrate a significant interaction between serum folate and MTHFR genotype in predicting homocysteine concentrations. One may consider that a differential response of homocysteine to folic acid supplementation may depend on MTHFR genotype which may have important implications when attempting to lower homocysteine concentrations in populations with mild folate deficiency. (C) 2003 Elsevier B.V. All rights reserved.