Genetic Variation in Vitamin D Pathway Is Tied to Colorectal Cancer Risk among African Americans


Get Permission

African Americans’ risk of colorectal cancer varies according to whether they have certain genetic variants that affect vitamin D metabolism, according to a study presented at the Fifth American Association for Cancer Research (AACR) Conference on The Science of Cancer Health Disparities, held recently in San Diego.1

Left-sided Colon Cancer Risk

In a research project led by Fabio Pibiri, PhD, postdoctoral associate at the University of Illinois at Chicago, genotyping of approximately 1,800 African-American subjects, half of whom had colorectal cancer, identified single nucleotide polymorphisms in two genes—the GC gene (which codes for a vitamin D–binding protein) and the CYP24A1 gene (which codes for an enzyme involved in degrading active vitamin D)—as significantly associated with the risk of left-sided colorectal cancer. However, no such associations were found for right-sided disease.

“We think that people who have polymorphism in the CYP24A1 gene express less of the enzyme this gene encodes, so that maybe they have higher levels of vitamin D, particularly in the left colon,” Dr. Pibiri commented in a press briefing. “So there is a difference in the protective effect of vitamin D between the right and left colon.” He added, “This is a nice hypothesis, and we are starting to test it right now in our laboratory. We have RNAs for all these samples. So we are pretty excited about these results, and we hope to clarify why there is this big difference in colorectal cancer risk.”

Clinical Application

William Nelson, MD, PhD, conference Co-Chair, press briefing moderator, and Director of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University in Baltimore, wondered if this new information can be applied clinically.

“One of the challenges in this country—as people are really starting to think about vitamin D and health—is whether this is a rationale for targeted supplementation,” Dr. Nelson commented. “You found African Americans with these particular [single nucleotide polymorphisms] who might be especially prone to developing colorectal cancer. Is this the kind of person in whom we should measure the vitamin D levels and, if they are low, then supplement them? Does that make sense?” he asked.

“Yes, it totally makes sense, talking about tailoring the different approaches to preventing cancer, depending on which race you belong to” and vitamin D status, Dr. Pibiri replied. He stressed that over 80% of circulating vitamin D depends on activation in the skin through exposure to ultraviolet light in sunshine. Thus, people with more darkly pigmented skin, as well as those living in northern latitudes, may have difficulty achieving adequate vitamin D levels. Moreover, it would be daunting to try to obtain sufficient amounts through typical dietary sources, such as milk, because very few dietary sources contain high levels of vitamin D.

“So we should consider this,” Dr. Pibiri maintained. “For example, taking 1,000 IU per day of vitamin D can be good for people in some southern parts of the United States and for whites. But maybe the black population, people with darker skin, and those who live in the northern part of this country should take 2,000 IU per day, or something like that.”

Study Rationale

Giving some background to the research, Dr. Pibiri noted that there is a substantial racial disparity in colorectal cancer, with African Americans having a higher incidence and mortality than whites.

“It is starting to be accepted that vitamin D is a protective factor against several types of cancer, especially colorectal cancer,” he continued. “Vitamin D is usually low in the serum of African-American people. We also think that genetic variants are present in vitamin D–related genes that may be associated with the higher risk that African Americans have for colorectal cancer.”

In the study, the investigators obtained samples from 292 patients with right-sided colorectal cancer, 443 patients with left-sided colorectal cancer, and 838 healthy individuals who served as controls. They opted to look at cancer sidedness because tumors arising in the right and left colon have differing characteristics, Dr. Pibiri explained. Additionally, the proportion of cancers that are left-sided is lower among African Americans than among whites.

Key Findings

The investigators tested for 39 putatively functional single nucleotide polymorphisms in a set of important genes involved in vitamin D synthesis and catabolism: CYP27A1, GC, CYP3A4, CYP2R1, DHCR7/NADSYN1, VDR, CYP27B1, and CYP24A1. The results showed that after adjustment for age and sex, none of the single nucleotide polymorphisms studied were associated with the risk of right-sided colorectal cancer. However, four were associated with the risk of left-sided colorectal cancer.

Specifically, the T base pair of the rs16847024 variant in the GC gene was associated with increased risk of left-sided disease (odds ratio = 1.56; P = .003), as was the G base of the rs6022990 variant in the CYP24A1 gene (odds ratio = 1.48; P = .006). The C base pair of the rs1155563 variant of the GC gene was associated with deceased risk of left-sided disease (odds ratio = 0.77; P = .039), as was the A base pair of rs73913755 variant of the CYP24A1 gene (odds ratio = 0.67; P = 1.9 × 10–4).

After additional adjustment for multivariate testing, only the last association remained statistically significant (P = .009), Dr. Pibiri reported. “Most of these single nucleotide polymorphisms are African American–specific, so they don’t exist in whites,” he pointed out.

The investigators plan a variety of related studies, according to Dr. Pibiri, including analysis of serum vitamin D levels in African American colorectal cancer, analysis of interactions between single nucleotide polymorphisms and vitamin D levels in African-American colorectal cancer, and determination of vitamin D gene-expression levels relative to genotype. ■

Disclosure: Drs. Nelson and Pibiri reported no potential conflicts of interest.

Reference

1. Pibiri F, Kittles RA, Sandler RS, et al: Genetic variation in the vitamin D pathway and risk for colorectal cancer in African Americans. Fifth AACR Conference on Cancer Health Disparities. Plenary Session 2. Presented October 28, 2012.



Advertisement

Advertisement



Advertisement