Associations between single nucleotide polymorphisms in folate uptake and metabolizing genes with blood folate, homocysteine, and DNA uracil concentrations.
BACKGROUND
Folate is an essential nutrient that supports nucleotide synthesis and biological methylation reactions. Diminished folate status results in chromosome breakage and is associated with several diseases, including colorectal cancer. Folate status is also inversely related to plasma homocysteine concentrations -- a risk factor for cardiovascular disease.


OBJECTIVE
We sought to gain further understanding of the genetic determinants of plasma folate and homocysteine concentrations. Because folate is required for the synthesis of thymidine from uracil, the latter accumulating and being misincorporated into DNA during folate depletion, the DNA uracil content was also measured.


METHODS
Thirteen single nucleotide polymorphisms (SNPs) in genes involved in folate uptake and metabolism, including folate hydrolase (FOLH1), folate polyglutamate synthase (FPGS), gamma-glutamyl hydrolase (GGH), methylene tetrahydrofolate reductase (MTHFR), methionine synthase (MTR), proton-coupled folate transporter (PCFT), and reduced folate carrier (RFC1), were studied in a cohort of 991 individuals.


RESULTS
The MTHFR 677TT genotype was associated with increased plasma homocysteine and decreased plasma folate. MTHFR 1298A>C and RFC1 intron 5A>G polymorphisms were associated with significantly altered plasma homocysteine concentrations. The FOLH1 1561C>T SNP was associated with altered plasma folate concentrations. The MTHFR 677TT genotype was associated with a approximately 34% lower DNA uracil content (P = 0.045), whereas the G allele of the GGH -124T>G SNP was associated with a stepwise increase in DNA uracil content (P = 0.022).


CONCLUSIONS
Because the accumulation of uracil in DNA induces chromosome breaks, mutagenic lesions, we suggest that, as for MTHFR C677T, the GGH -124 T>G SNP may modulate the risk of carcinogenesis and therefore warrants further attention.
Eberly College of Science, Pennsylvania State University, University Park, PA, USA.
Lauren
L
DeVos
Aurelie
A
Chanson
Zhenhua
Z
Liu
Eric D
ED
Ciappio
Laurence D
LD
Parnell
Joel B
JB
Mason
Katherine L
KL
Tucker
Jimmy W
JW
Crott
D000368:Aged; D002869:Chromosome Aberrations; D015331:Cohort Studies; D004249:DNA Damage / Q000235:genetics; D019175:DNA Methylation; D005260:Female; D005492:Folic Acid / Q000097:blood / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic; D006710:Homocysteine / Q000097:blood*; D006801:Humans; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics*; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D014498:Uracil / Q000378:metabolism*
D026901:Membrane Transport Proteins; D006710:Homocysteine; D014498:Uracil; D005492:Folic Acid; D042965:Methylenetetrahydrofolate Reductase (NADPH2)