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.


METHODS
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-->T and 1298A-->C, methionine synthase reductase (MTRR) 66A-->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-->T 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 microg/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-->T and MTRR 66A-->G on serum homocysteine concentrations among non-Hispanic whites.


CONCLUSIONS
The MTHFR 677C-->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-->T on homocysteine concentrations was reduced by moderate daily folic acid intake.
Yang
Quan-He
QH
National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, Atlanta, GA 30341, USA. qay0@cdc.gov
Botto
Lorenzo D
LD
Gallagher
Margaret
M
Friedman
J M
JM
Sanders
Christopher L
CL
Koontz
Deborah
D
Nikolova
Stanimila
S
Erickson
J David
JD
Steinberg
Karen
K
D019731:Carbon-Nitrogen Ligases / Q000235:genetics*; D003541:Cystathionine beta-Synthase / Q000235:genetics*; D005006:Ethnicity; D005287:Ferredoxin-NADP Reductase / Q000235:genetics*; D005492:Folic Acid / Q000008:administration & dosage / Q000097:blood*; D005527:Food, Fortified; D014644:Genetic Variation; D005838:Genotype; D006710:Homocysteine / Q000097:blood*; D006801:Humans; D054647:Nutrigenomics; D009749:Nutrition Surveys; D011110:Polymorphism, Genetic; D015995:Prevalence; D014481:United States
D006710:Homocysteine; D005492:Folic Acid; C111241:methionine synthase reductase; D005287:Ferredoxin-NADP Reductase; D003541:Cystathionine beta-Synthase; D019731:Carbon-Nitrogen Ligases; C021557:5,10-methenyltetrahydrofolate synthetase