|Devos, Lauren - PENN STATE UNIVERSITY|
|Chanson, Aurelie - JM USDA HNRCA @ TUFTS|
|Liu, Zhenhua - JM USDA HNRCA @ TUFTS|
|Ciappo, Eric - JM USDA HNRCA @ TUFTS|
|Crott, Jimmy - JM USDA HNRCA @ TUFTS|
Submitted to: American Journal of Clinical Nutrition
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: July 11, 2008
Publication Date: October 1, 2008
Citation: Devos, L., Chanson, A., Liu, Z., Ciappo, E., Parnell, L.D., Mason, J.B., Tucker, K., Crott, J.W. 2008. Associations between single nucleotide polymorphisms in folate uptake and metabolizing genes with blood folate, homocysteine and DNA uracil concentrations. American Journal of Clinical Nutrition. 88(4):1149-1158. Interpretive Summary: Folate is an essential vitamin which supports the synthesis of new genetic material and its modification by the process of “methylation”. Low folate intake has been associated with an increased risk for several cancers, especially colorectal cancer. We sought to determine whether specific changes in folate-related genes affect blood levels of folate, a related metabolite called homocysteine and levels of DNA damage in blood cells. We found that two mutations were associated with altered blood folate, 3 with altered blood homocysteine concentrations and 2 with altered DNA composition. These changes in DNA composition are very interesting and require further investigation as they may translate into altered risk for cancer.
Technical Abstract: Background: Folate is an essential nutrient which 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 mis-incorporated into DNA during folate depletion, DNA uracil content was also measured. Design: Thirteen single nucleotide polymorphisms (SNPs) in genes involved in folate uptake and metabolism were studied in a cohort of 991 individuals; 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). 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. The MTHFR 677TT genotype was associated with a approx. 34% lower DNA uracil content (P = 0.045) while the G allele of the GGH -124T>G SNP was associated with a stepwise increase in DNA uracil content (P=0.022). Conclusion: Because the accumulation of uracil in DNA induces chromosome breaks, a mutagenic lesion, we suggest that, like MTHFR C677T, the GGH -124 T>G SNP may modulate risk for carcinogenesis and therefore warrants further attention.