Prevalence and effects of gene-gene and gene-nutrient interactions on serum folate and serum total homocysteine concentrations in the United States: findings from the third National Health and Nutrition Examination Survey DNA Bank

Background: Abnormalities of folate and homocysteine metabolism are associated with a number of pediatric and adult disorders. Folate intake and genetic polymorphisms encoding folate-metabolizing enzymes influence blood folate and homocysteine concentrations, but the effects and interactions of these factors have not been studied on a population-wide basis. Objective: The objective was to assess the prevalence of these genetic polymorphisms and their relation to serum folate and homocysteine concentrations. Design: DNA samples from 6793 participants in the third National Health and Nutrition Examination Survey (NHANES III) during 1991-1994 were genotyped for polymorphisms of genes coding for folate pathway enzymes 5,10-methylenetetrahydrofolate reductase (MTHFR) 677C[right arrow]T and 1298A[right arrow]C, methionine synthase reductase (MTRR) 66A[right arrow]G, and cystathionine-[beta]-synthase 844ins68. The influence of these genetic variants on serum folate and homocysteine concentrations was analyzed by age, sex, and folate intake in 3 race-ethnicity groups. Results: For all race-ethnicity groups, serum folate and homocysteine concentrations were significantly related to the MTHFR 677C[right arrow]T genotype but not to the other polymorphisms. Persons with the MTHFR 677 7T genotype had a 22.1% (95% CI: 14.6%, 28.9%) lower serum folate and a 25.7% (95% CI: 18.6%, 33.2%) higher homocysteine concentration than did persons with the CC genotype. Moderate daily folic acid intake (mean: 150 [micro]/d; 95 % CI: 138, 162) significantly reduced the difference in mean homocysteine concentrations between those with the MTHFR 677 CC and TT genotypes. We found a significant interaction between MTHFR 677C [right arrow] T and MTRR 66A [right arrow] G on serum homocysteine concentrations among non-Hispanic whites. Conclusions: The MTHFR 677C [right arrow] T polymorphism was associated with significant differences in serum folate and homocysteine concentrations in the US population before folic acid fortification. The effect of MTHFR 677C [right arrow] T on homocysteine concentrations was reduced by moderate daily folic acid intake.