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Polymorphisms in uracil-processing genes, but not one-carbon nutrients, are associated with altered DNA uracil concentrations in an urban Puerto Rican population^1,2,3

¹ From the Jean Mayer US Department of Agriculture, Human Nutrition Research Center on Aging at Tufts University, Boston, MA (AC, LDP, ZL, JWC, KLT, and JBM), and the Friedman School of Nutrition Science and Policy, Tufts University, Boston, MA (EDC).

² This material is based on work supported by the US Department of Agriculture, Agricultural Research Service, under agreement no. 58-1950-7-707; by grants from the NRI, CSREES, USDA under award no. 2009-35200-05016 (to AC); and by grants NIH P01 AG023394 (to KLT) and K05 CA100048 (to JBM).

³ Address correspondence to JB Mason, Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, 711 Washington Street, Boston, MA 02111. E-mail: joel.mason{at}tufts.edu.

ABSTRACT

Background: Five genes—UNG, SMUG1, MBD4, TDG, and DUT—are involved in the repair or prevention of uracil misincorporation into DNA, an anomaly that can cause mutagenic events that lead to cancer. Little is known about the determinants of uracil misincorporation, including the effects of single nucleotide polymorphisms (SNPs) in the abovementioned genes. Because of their metabolic function, folate and other one-carbon micronutrients may be important factors in the control of uracil misincorporation.

Objectives: We sought to identify polymorphisms in uracil-processing genes that are determinants of DNA uracil concentration and to establish whether one-carbon nutrient status can further modify their effects.

Design: We examined the relations between 23 selected variants in the 5 uracil-processing genes, uracil concentrations in whole-blood DNA, and one-carbon nutrient (folate, vitamins B-6 and B12, and riboflavin) status in 431 participants of the Boston Puerto Rican Health Study.

Results: Four SNPs in DUT, UNG, and SMUG1 showed a significant association with DNA uracil concentration. The SNPs in SMUG1 (rs2029166 and rs7296239) and UNG (rs34259) were associated with increased uracil concentrations in the variant genotypes (P = 0.011, 0.022, and 0.045, respectively), whereas the DUT SNP (rs4775748) was associated with a decrease (P = 0.023). In this population, one-carbon nutrient status was not associated with DNA uracil concentration and it did not modify the effect of these 4 identified SNPs.

Conclusion: Because elevated uracil misincorporation may induce mutagenic lesions, possibly leading to cancer, we propose that the 4 characterized SNPs in DUT, UNG, and SMUG1 may influence cancer risk and therefore deserve further investigation.

Received for publication January 2, 2009. Accepted for publication March 23, 2009.