Genetic variation in the sodium dependent vitamin C transporters, SLC23A1 and SLC23A2 and colorectal adenoma Free

5804

Vitamin C is an essential co-factor for at least eight distinct enzymatic pathways including intracellular oxidative-reductive balance and host defenses. In colon cancer tissue, the levels of non-enzymatic antioxidant parameters, such as vitamin C, vitamin E and glutathione are significantly decreased whereas lipid-peroxidation is enhanced. Past epidemiological cohort and case-control studies as well as intervention trials have suggested a protective effect of vitamin C for colorectal adenoma and cancer development. The primary mechanism of vitamin C transport is facilitated by two sodium-dependent vitamin C transporters, SLC23A1 and SLC23A2. We investigated the association of common single nucleotide polymorphisms (SNPs) in both genes with colorectal adenoma, a known risk for cancer. SNPs were previously identified by resequencing in a multiethnic population and analyzed in a case-control study nested within the screening arm of the Prostate, Lung, Colorectal, and Ovarian Cancer Screening (PLCO) Trial consisting of 656 Caucasian cases with advanced colorectal adenoma and 665 Caucasian controls with a negative sigmoidoscopy result. SLC23A1 controls bulk absorption and is localized to intestine, liver, and kidney, whereas SLC23A2 is responsible for generalized vitamin C accumulation in most tissues. High frequency SNPs in both genes were analyzed by TaqMan (n=5 in SLC23A1 and n=11 in SLC23A2). The two genes share high sequence similarity for the coding regions but differ substantially in the size of the genes. In the control populations, we confirmed that the linkage disequilibrium across SLC23A1 is strong whereas across SLC23A2, there are, at least, several blocks. Haplotype analysis was limited in SLC23A2, but more robust in SLC23A1. The results of the SLC23A1 analysis (by haplotype and single SNP) were unremarkable: no associations were observed. A 2 SNP haplotype in SLC23A2 (intron 8 and exon 11, which lie 10 kb apart; frequency in controls=8.3%) showed a significant protective association with advanced colorectal adenoma, (OR 0.49, 95% CI 0.25, 0.95 comparing G-C haplotype with most common haplotype C-C). Both SNPs are common (minor allele frequency > 30%) and they are in linkage disequilibrium (D’ = 0.89, 95% CI 0.86, 0.92). Further analysis is needed to probe the genetic and functional basis of this finding in SLC23A2 and to evaluate interactions with exogenous (dietary) factors in colorectal carcinogenesis.