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

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 B-12, 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.

Figures

FIGURE 1

Mean (±SEM) blood DNA uracil concentrations by TT (n = 275), TG (n = 131), and GG (n = 25) genotypes for the rs4775748 single nucleotide polymorphism in DUT. *Log uracil was significantly different (P = 0.029, general linear model) from the other 2 genotypes combined (recessive model). The P values were 0.023 after adjustment for age, sex, riboflavin intake, and plasma folate, vitamin B-12, and vitamin B-6 and 0.027 after further adjustment for population admixture.

FIGURE 2

Mean (±SEM) blood DNA uracil concentrations by genotype for the rs2029166 and rs7296239 single nucleotide polymorphisms (SNPs) in SMUG1. SNP rs2029166: n = 172, 206, and 50 for the CC, CT, and TT genotypes, respectively. SNP rs7296239: n = 127, 227, and 77 for the TT, TC, and CC genotypes, respectively. *Log uracil was significantly different (P < 0.05, general linear model) from the other 2 genotypes combined (recessive model). The unadjusted P values were 0.022 and 0.017 for SNPs rs2029166 and rs7296239, respectively. The P values were 0.011 and 0.022, respectively, after adjustment for age, sex, riboflavin intake, and plasma folate, vitamin B-12, and vitamin B-6 and 0.013 and 0.022, respectively, after further adjustment for population admixture.

FIGURE 3

Mean (±SEM) blood DNA uracil concentrations by GG (n = 224), GC (n = 169), and CC (n = 33) genotypes for the rs34259 single nucleotide polymorphism in UNG. Log uracil was significantly different (P for trend = 0.033, general linear model) between the 3 genotypes (additive model). The P values were 0.045 after adjustment for age, sex, riboflavin intake, and plasma folate, vitamin B-12, and vitamin B-6 and 0.064 after further adjustment for population admixture.