Submitted to: American Journal of Clinical Nutrition
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 3/16/2009
Publication Date: 6/1/2009
Citation: Chanson, A., Parnell, L.D., Ciappio, E.D., Liu, Z., Crott, J.W., Tucker, K., Mason, J.B. 2009. Polymorphisms in uracil-processing genes, but not one-carbon nutrients, are associated with altered DNA uracil concentrations in an urban Puerto Rican population. American Journal of Clinical Nutrition. 89:1927-1936. Interpretive Summary: DNA is a polymer composed of four deoxyribonucleotide units with a nitrogenous base of adenine, guanine, thymine or cytosine. Under certain conditions, uracil can mistakenly be incorporated into the DNA chain. Uracil, a normal constituent of genetic polymers other than DNA, can promote sequence-changing mutations once incorporated into the DNA chain. Five human genes (UNG, SMUG1, MBD4, TDG and DUT) are involved in repair or prevention of uracil misincorporation into DNA, an anomaly that can promote events leading to cancer. Because of their metabolic function, folate and other related one-carbon nutrients may be important factors in the control of uracil misincorporation. Thus, we examined the relationships between 23 selected genetic variants in the five uracil-processing genes, blood DNA uracil concentration and one-carbon nutrient (folate, riboflavin and vitamins B6 and B12) status in 431 participants of the Boston Puerto Rican Health Study. Four of these variants, in genes DUT, UNG and SMUG1, showed a statistically significant relationship with the level of uracil in DNA, whose presence in DNA can act as a predecessor to cancer. One-carbon nutrient status of the individuals, however, exerted no observed effects on DNA uracil concentrations nor on the relationships of the above four variants. In conclusion, evidence is presented to suggest that these four genetic variants may have an impact on cancer risk.
Technical Abstract: Background. Five genes - UNG, SMUG1, MBD4, TDG and DUT - are involved in repair or prevention of uracil misincorporation into DNA, an anomaly that can cause mutagenic events leading to cancer. Little is known about the determinants of uracil misincorporation, including the effects of single-nucleotide polymorphisms (SNPs) in the above mentioned genes. Because of their metabolic function, folate and other inter-related one-carbon nutrients 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 relationships between 23 selected variants in the five uracil-processing genes, blood DNA uracil concentration and one-carbon nutrient (folate, B6, B12, riboflavin) status in 431 participants of the Boston Puerto Rican Health Study. Results. Four SNPs in DUT, UNG and SMUG1 showed significant association with DNA uracil concentration. The SNPs in SMUG1 (rs2029166 and rs7296239) and UNG (rs34259) were associated with increased uracil concentration in the variant genotypes (P= 0.011, 0.022 and 0.045, respectively), while the DUT SNP (rs4775748) was associated with a decrease (P= 0.023). In this population, one-carbon nutrient status was neither associated with DNA uracil concentration, nor did it modify the effect of these four identified SNPs. Conclusions. Since elevated uracil misincorporation may induce mutagenic lesions, possibly leading to cancer, we propose that the four characterized SNPs in DUT, UNG and SMUG1 may impact on cancer risk, and therefore deserve further investigation.