Associations between vitamin D, vitamin D receptor gene and the androgen receptor gene with colon and rectal cancer

Abstract

The transcriptional activity of the vitamin D receptor (VDR) gene is regulated, at least in part, by the androgen receptor (AR) gene. We evaluate how the number of polyglutamine (CAG) repeats of the AR gene influence colorectal cancer in conjunction with vitamin D, sunshine exposure and VDR. Studies of colon (1,580 cases and 1,968 controls) and rectal (797 cases and 1,016 controls) cancer were used. Vitamin D intake and average hours of sunshine exposure interacted with AR genotype in men. Men with low vitamin D intake or low levels of sunshine exposure who had 231 CAG repeats of the AR gene had the greatest risk of colon cancer. ORs for men with 23 or more CAG repeats of the AR gene and in the lowest tertile of vitamin D intake or sunshine exposure were 1.71 (95% CI 1.14, 2.56) and 1.51 (95% CI 1.09, 2.09). Men with high levels of sunshine exposure were at reduced risk of developing rectal cancer if they had 23 or more CAG repeats (OR 0.62 95% CI 0.39, 0.97) than if they had fewer than 23 CAG repeats. The FF genotype of the Fok1 VDR gene was associated with reduced risk of colon cancer among women with any allele of 231 CAG repeats (OR 0.62 95% CI 0.44, 0.88), whereas men with the LL/bb VDR genotypes were at reduced risk of rectal cancer if they also had 231 CAG repeats (OR 0.71 95% CI 0.48, 1.05) relative to men with fewer than 23 CAG repeats of the AR gene. These data provide support for the role of vitamin D and sunshine exposure in the etiology of colorectal cancer and suggest that AR gene may modulate the association. Vitamin D has been associated inconsistently with colorectal cancer. 10 Differences in relative risk could stem from many sources, including sunshine, a major source of vitamin D, not being considered as part of the risk factor equation. Several investigators have studied sunshine exposure independently to better understand the associations between vitamin D and colorectal cancer. 11-13 Polymorphisms of the VDR gene have also been studied in conjunction with colorectal cancer and adenomas, since it may play a key role in vitamin D signaling, which could further influence colorectal cancer risk. [14][15][16][17][18][19] Polymorphisms of the VDR gene that have been studied include a poly A repeat at the 3 0 untranslated region (3 0 UTR) of the gene, 2 polymorphisms at intron 8 (Bsm I and Apa I) and 1 in exon 9 (Taq I) that are in linkage-disequilibrium with each other. 17,20 These polymorphisms, either alone or in combination, have been associated with increased mRNA expression of the VDR gene and increased serum levels of 1,25-dihydroxy vitamin D. 21,22 At the start site of the gene, a polymorphism detected with a Fok I digest has also been studied and has been shown to be not in linkage disequilibrium with the other variants. 17 A study conducted in human fibroblast cell lines found higher vitamin D hormone activity for the F allele than for the f allele. 23 One study showed that the ff genotype of the Fok I polymorphism increased risk of colorectal cancer, 18 whereas another showed that it w...

Polymorphic CAG Repeat and Protein Expression of Androgen Receptor Gene in Colorectal Cancer

“…We studied 550 patients with colorectal cancer without somatic alterations in CAG repeats, and demonstrated that long CAG repeats of the AR genotype were associated with higher (1.293-fold in males, 1.255-fold in females, and 1.277-fold in total colorectal cancer population, respectively) risk for colorectal cancer in a Chinese population, whereas a short CAG repeat sequence may provide a certain degree of protection against colorectal cancer. Our study was different from that of Slattery and colleagues (13), who found that the AR genotype can decrease the risk for rectal cancer between patients and controls if the genotype possesses a short CAG repeat length. We also obtained a different cut-off point of CAG repeat length, which might attribute to different regions and ethnicities.…”

“…Primers (13) were AR-Forward 5 0 -GTTTCTGTGGGGCCTCTAC-GATGG-3 0 and AR-Reverse 5 0 -GTTTCTGCGCGAAGTGATCCA-GAA-3 0 . AR-Forward was fluorescently labeled with 6-carboxyfluorescine (FAM).…”

Meta-Analyses of Vitamin D Intake, 25-Hydroxyvitamin D Status, Vitamin D Receptor Polymorphisms, and Colorectal Cancer Risk

“…Interactions between the VDR gene and other genes have also been suggested. For instance, the androgen receptor gene could interact with the Fok1 VDR polymorphism and the sunlight exposure and vitamin D intake (62).…”

Vitamin D Receptor Gene Variation, Dietary Intake and Bone Mineral Density in Obese Women: A Cross Sectional Study

“…3). Several investigations reported that the gene VDR and FOK1 FF genotype with respect to the higher vitamin D consumption reduces the risk of colon cancer (45), breast cancer (46), and skin cancer (47) among women. Our study suggests that interactions between FOK1 polymorphism in Iranian obese women and dietary intake of calcium and vitamin D play a major role in bone mineral density and osteoporosis.…”