Genetic Variation in Sodium-Dependent Vitamin C Transporters SLC23A1 and SLC23A2 and Risk of Advanced Colorectal Adenoma

Abstract

Previous observational studies suggest that vitamin C may reduce risk of colorectal cancer. Vitamin C transport is facilitated by membrane bound sodium-dependent transporters, SVCT1 (encoded by SLC23A1) and SVCT2 (encoded by SLC23A2). To investigate if common genetic variants in these two genes are associated with risk of colorectal tumor development, we conducted a case-control study of 656 Caucasian advanced distal colorectal adenoma cases and 665 Caucasian sigmoidoscopy-negative controls nested within the screening arm of the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. The analysis of common single nucleotide polymorphisms in SLC23A1 revealed no association. For SLC23A2, overall, there was no association with haplotypes, but two SNPs located in intron 8 and exon 11 could be associated (odds ratio = 0.49, 95% confidence interval = 0.25–0.95 for haplotype G-C vs. haplotype C-C). The findings should be confirmed in follow-up studies, and further investigation is required to probe the functional basis of this finding.

Notes

^a Abbreviations are as follows: SNP, single nucleotide polymorphism; dbSNP, the single nucleotide polymorphism database; SLC23A1, solute carrier family 23 (nucleobase transporters), member 1; SLC23A2, SLC23A member 2; Ex, exon; In, intron. Table shows minor allele frequency in the Caucasian control population. The exonic SNP in exon 8, SLC23A1-05 are nonsynonymous (i.e., changes the amino-acid from valine to methionine at position 264). The exonic SNPs in SLC23A2 exon 6 and 11 are synonymous. All variants are in Hardy-Weinberg equilibrium (HWE).

^a Abbreviations are as follows: SLC23A1, solute carrier family 23 (nucleobase transporters), member 1; SLC23A2, SLC23A member 2; SNP, single nucleotide polymorphism; OR, odds ratio; CI, confidence interval. Distal defined as descending, sigmoid colon or rectum; advanced adenoma defined as large (> 1 cm) or high-grade dysplasia, or villous elements (including tubulo-villous adenomas).

^a Abbreviations are as follows: SLC23A1, solute carrier family 23 (nucleobase transporters), member 1; SLC23A2, SLC23A member 2; SNP, single nucleotide polymorphism.

^b Global test for association between haplotypes and colorectal adenoma.

^c In SLC23A1, analysis by block structure as defined by Gabriel et al. (29). In SLC23A2, no haplotype blocks as defined by Gabriel et al. were identified. A sliding window of regions displaying high degree of linkage disequilibrium were utilized for exploratory analyses.

^a Abbreviations are as follows: SLC23A1, solute carrier family 23 (nucleobase transporters), member 1; SLC23A2, SLC23A member 2; OR, odds ratio; CI, confidence interval.

^b Adjusted for age, sex, clinical center, and ethnicity.

^c Overall haplotype test likelihood ratio test P = 0.11 (exact test).

^a Abbreviations are as follows: OR, odds ratio; CI, confidence interval.

^b Reference category.

^c Adjusted for age; center; gender; energy intake; ethnic origin; educational attainment; tobacco use; alcohol intake; aspirin and ibuprofen use; physical activity; body mass index; and intake of red meat, folate, calcium, and dietary fiber.