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Newswise — SAN DIEGO — African-Americans are more likely than non-Hispanic whites to have and die from colorectal cancer. Changes in the DNA sequence of genes that affect how the body makes and destroys vitamin D modify the risk for colorectal cancer in African-Americans, according to data presented at the Fifth AACR Conference on The Science of Cancer Health Disparities, held here Oct. 27-30, 2012.
“Vitamin D deficiency is associated with a higher risk for colorectal cancer,” said Fabio Pibiri, Ph.D., a postdoctoral associate at the University of Illinois at Chicago. “Because increased skin pigment lowers the amount of ultraviolet light that can be used to make vitamin D in the skin, more African-Americans than whites are vitamin D-deficient, putting them at higher risk for colorectal cancer. Our research showed that genetic differences may play an important role as well.”
Pibiri and colleagues evaluated 39 single nucleotide polymorphisms (SNPs), DNA sequence variations, in vitamin D-related genes in 1,799 African-Americans — 961 patients with colorectal cancer and 838 controls — who participated in the North Carolina Colorectal Cancer Study and the Chicago Colorectal Cancer Consortium.
They found several SNPs in genes involved in the generation and destruction of vitamin D that were associated with colorectal cancer.
One variation in the gene that tells a cell to make the protein that destroys vitamin D was linked to protection from developing colorectal cancer on the left side of the body. According to Pibiri, this variation is specific to African-Americans and the finding may explain why African-Americans have a lower proportion of left-sided colorectal cancer compared with right-sided colorectal cancer.
“It seems likely that these differences in the DNA sequence alter the function of the vitamin D-related genes,” said Pibiri. “For example, we hypothesize that the genetic variation linked to protection decreases levels of the vitamin D-destroying protein. Now all we need to do is show that.”
The National Institutes of Health, the American Institute for Cancer Research and the American Cancer Society Illinois Division provided funding for this research.
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ABSTRACT:Genetic variation in the vitamin D pathway and risk for colorectal cancer in African Americans. Fabio Pibiri1, Rick A. Kittles1, Robert S. Sandler2, Temitope O. Keku2, Sonia S. Kupfer3, Rosa Xicola1, Xavier Llor1, Nathan A. Ellis1. 1University of Illinois at Chicago, Chicago, 2University of North Carolina, Chapel Hill, 3University of Chicago, Chicago, IL.
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, 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.
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