Abstract 1330: Genetic variation in the vitamin D pathway and risk for colorectal cancer in African Americans.

Abstract

Abstract Background: Colorectal cancer (CRC) is the third leading cause of cancer-related deaths in both sexes in the United States. There is a large disparity in both CRC incidence and survival between African Americans (AAs) and all other US racial groups. Differences in serum vitamin D levels could contribute to this disparity because vitamin D is thought to protect against CRC and AAs have lower serum vitamin D levels than whites. We hypothesized that genetic variants in vitamin D-related genes are associated with CRC risk in AAs. Methods: To evaluate association with CRC risk, we genotyped 39 putatively functional single nucleotide polymorphisms (SNPs) in vitamin D-related genes (CYP27A1, GC, CYP3A4, CYP2R1, DHCR7/NADSYN1, VDR, CYP27B1 and CYP24A1, in 961 AA cases (292 right colon, 340 left colon, 113 rectal) and 838 AA controls from the North Carolina Colorectal Cancer Study and the Chicago Colorectal Cancer Consortium. We calculated odds ratios (OR) using logistic regression, assuming an additive genetic model and controlling for age, gender, and West African ancestry. We further evaluated whether the genetic polymorphisms conferred differential risk for right-sided CRC (R-CRC) and left-sided CRC (L-CRC, including rectal). Results: Nominal associations (p<0.05) were detected between CRC and SNPs in the 24-hydroxylase gene CYP24A1, rs73913755 (OR, 0.73; P = 0.0003), which degrades calcidiol, and the 25-hydroxylase gene CYP2R1, rs12794714 (OR, 0.82; P = 0.032), which converts cholecalciferol into calcidiol. When we analyzed R-CRC and L-CRC separately, no SNPs were associated with R-CRC, whereas 4 SNPs were associated with L-CRC. Two SNPs in the vitamin D binding protein gene GC, rs1155563 (OR, 0.77; P = 0.039) and rs16847024 (OR, 1.56; P = 0.003) and two SNPs in the 24-hydroxylase gene CYP24A1, rs6022990 (OR, 1.48; P = 0.006) and rs73913755 (OR, 0.67; P = 0.0002). The P value for rs73913755 was statistically significant after adjustment for multiple testing. Conclusion: Our results indicate that several SNPs in the vitamin D pathway contribute to CRC susceptibility in AAs. The minor allele of rs73913755 was present in at least one dose in 48% of AA controls and only 30% of cases, conferring increased protection against L-CRC. We hypothesize that the minor allele of rs73913755 causes a reduction in the expression levels of CYP24A1. Because rs73913755 is African-specific, showing high Fst value in comparison to ancestrally European populations, its presence could explain in part the lower proportion of L-CRC in AAs compared to whites. Future studies include analysis of vitamin D pathway gene expression levels relative to genotype and analysis of possible gene-vitamin D level interactions in AA CRC. Citation Format: Fabio Pibiri, Nathan Ellis, Rick Kittles, Xavier LLor, Rosa Xicola, Sonia Kupfer, Robert S. Sandler, Temitope Keku. Genetic variation in the vitamin D pathway and risk for colorectal cancer in African Americans. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1330. doi:10.1158/1538-7445.AM2013-1330