Submitted to: American Association of Cancer Research Meeting
Publication Type: Abstract Only
Publication Acceptance Date: 1/1/2008
Publication Date: 4/1/2008
Citation: Chanson, A., Parnell, L.D., Crott, J., Choi, S., Han, H., Mason, J.B. 2008. Genetic variants in uracil processing enzymes are associated with abnormal DNA uracil content. American Association for Cancer Research (AACR) 2008 Annual Meeting, April 12-16, 2008. Paper No. 1891. Interpretive Summary:
Technical Abstract: Introduction. Maintenance of DNA integrity through DNA repair is critical in cancer prevention. Among the enzymes involved in DNA repair are those that prevent or correct uracil misincorporation in DNA. Repair of misincorporated uracil is important since it can cause double-stranded DNA breaks and other mutagenic events that can initiate or promote carcinogenesis. Also relevant is the B-vitamin folate as it is a co-factor in the enzymatic conversion of uracil to thymidine, and its deficiency promotes uracil misincorporation in DNA. Moreover, folate and other B vitamins are implicated as factors modulating cancer risk. Five genes encode the enzymes involved in uracil-repair in humans, for which many single nucleotide polymorphisms (SNPs) have been identified. However, their phenotypes have not yet been explored. Our goal is to identify SNPs in uracil processing genes that are determinants of DNA uracil levels, and to study how B vitamin status affects these relationships. Methods. Twenty-two SNPs were selected with a bioinformatics approach that identified variants with probable functional consequences and from distinct linkage groups. Association between SNP genotypes and uracil levels in blood DNA was tested in a cohort of 91 unrelated South Koreans. Results. Multiple linear regression analyses showed that five SNPs in two of the uracil-repair genes were significantly associated with uracil levels. Four of them were associated with an increase in uracil in the homozygous variant individuals compared to the homozygous wild-type subjects, and one was associated with a decrease (see table). Four SNPs were located in non-coding regions whereas one was a non-synonymous SNP within an exon that is predicted to change the protein sequence. No interactions between B vitamin levels, SNP genotypes and uracil levels were found in this study. Conclusion. We identified 5 SNPs with a biochemical phenotype that may impact on cancer risk. We are presently confirming our observations in a larger study.