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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^1,2,3,4

¹ From the National Center on Birth Defects and Developmental Disabilities (Q-HY and JDE), the National Center for Environmental Health (MG, DK, and SN), and the Coordinating Center for Health Promotion (KS), Centers for Disease Control and Prevention, Atlanta, GA; the Department of Pediatrics, University of Utah, Salt Lake City, UT (LDB); the Department of Medical Genetics, University of British Columbia, Vancouver, Canada (JMF); and the Harris Corporation/National Center of Health Statistics, Centers for Disease Control and Prevention, Hyattsville, MD (CLS)

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) 677CT and 1298AC, methionine synthase reductase (MTRR) 66AG, and cystathionine-β-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 677CT genotype but not to the other polymorphisms. Persons with the MTHFR 677 TT 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 µg/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 677CT and MTRR 66AG on serum homocysteine concentrations among non-Hispanic whites.

Conclusions: The MTHFR 677CT polymorphism was associated with significant differences in serum folate and homocysteine concentrations in the US population before folic acid fortification. The effect of MTHFR 677CT on homocysteine concentrations was reduced by moderate daily folic acid intake.