Abstract PR02: Genetic variation in the vitamin D pathway and risk for colorectal cancer in African Americans.
Authors: Pibiri Fabio , Kittles Rick A. , Sandler Robert S. , Keku Temitope O. , Kupfer Sonia S. , Xicola Rosa , Llor Xavier , Ellis Nathan A. 
Published: August 2014

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&lt;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, with the minor allele of rs73913755 conferring increased protection against L-CRC. We hypothesize that the minor allele of rs73913755 causes a reduction in the expression levels of CYP24A1. We further hypothesize that there is a gradient of expression levels of CYP24A1 in the colon with higher levels on the left side than on the right side. The protective effect of rs73913755 would then be explained by increased levels of calcidiol in the tissue in combination with a threshold effect. Because rs73913755 is African-specific, 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.

This abstract is also presented as Poster B72.

Citation Format: Fabio Pibiri, Rick A. Kittles, Robert S. Sandler, Temitope O. Keku, Sonia S. Kupfer, Rosa Xicola, Xavier Llor, Nathan A. Ellis. Genetic variation in the vitamin D pathway and risk for colorectal cancer in African Americans. [abstract]. In: Proceedings of the Fifth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2012 Oct 27-30; San Diego, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2012;21(10 Suppl):Abstract nr PR02.