(ChemotherapyAdvisor) – Several single nucleotide polymorphisms (SNPs) in the vitamin D pathway contribute to colorectal cancer (CRC) susceptibility in African Americans, results of a genotyping study reported during the Fifth AACR Conference on The Science of Cancer Health Disparities, San Diego, CA, has found.
Specifically, “the minor allele of rs73913755 conferred increased protection against left-sided CRC,” including rectal, noted Fabio Pibiri, of the University of Illinois at Chicago, Chicago, IL. “We hypothesize that the minor allele of rs73913755 causes a reduction in the expression levels of CYP24A1,” leading to a gradient of expression levels of CYP24A1 in the colon, with higher levels on the left 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,” he added. The rs73913755 minor allele is African-specific and could account, in part, for the lower proportion of left-sided CRC in African Americans vs whites.
The investigators genotyped 39 putatively functional SNPs in vitamin D-related genes (CYP27A1, GC, CYP3A4, CYP2R1, DHCR7/NADSYN1, VDR, CYP27B1 and CYP24A1) to evaluate association with CRC risk in 961 African American cases (292 right colon, 340 left colon, 113 rectal) and 838 African American controls from the North Carolina Colorectal Cancer Study and the Chicago Colorectal Cancer Consortium.
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 right-sided and left-sided CRC were analyzed separately, no SNPs were associated with right-sided CRC, “whereas 4 SNPs were associated with left-sided-CRC,” Dr. Pibiri stated, two 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 in the 24-hydroxylase gene CYP24A1, rs6022990 (OR 1.48; P=0.006) and rs73913755 (OR 0.67; P=0.0002).
Future studies include analysis of vitamin D pathway gene expression levels relative to genotype and analysis of possible gene-vitamin D level interactions in African American CRC.