Dietary calcium, vitamin D, VDR genotypes and colorectal cancer

Abstract

The vitamin D receptor (VDR) may importantly modulate risk of colorectal cancer either independently or in conjunction with calcium and vitamin D intake. We evaluate the association between calcium, vitamin D, dairy products, and VDR polymorphisms in 2 case-control studies of colon and rectal cancer (n ‫؍‬ 2,306 cases and 2,749 controls). Dietary intake was evaluated using a detailed diet history questionnaire. Two VDR polymorphisms were evaluated: an intron 8 Bsm 1 polymorphism and a 3 untranslated region poly-A length polymorphism (designated S for short and L for long Uncontrolled cell growth is central to the carcinogenic process. Factors that regulate and control cell growth and proliferation may be important to the etiology of cancer. In the intestine, the active vitamin D metabolite, 1,25 (OH) 2 D3 is involved in regulating cell proliferation and differentiation. 1 It also has been suggested that vitamin D may have an important role in determining the effects of calcium on colorectal epithelial proliferation. 2 Epidemiological studies, although mixed in their assessment of the associations between calcium and vitamin D and colorectal cancer, provide support for high intakes of calcium and vitamin D being inversely related to colorectal cancer. [3][4][5][6][7][8] The protective effects of calcium have been strengthened by observations from clinical trials showing significant reduction in adenoma recurrence with calcium supplementation. 9,10 These studies further suggest that these associations may be stronger for distal rather than proximal colon tumors and may vary by age at diagnosis. 7,11,12 The vitamin D receptor (VDR), a nuclear hormone receptor, is essential for vitamin D action and calcium homeostasis. Several polymorphisms of the VDR gene have been identified, including 2 restriction fragment length polymorphisms (RFLPs) in intron 8 (Bsm I and Apa I) and one in exon 9 (Taq I). These are in linkage disequilibrium with each other and with several 3Ј untranslated region (3Ј UTR) polymorphisms, including a poly A repeat. 13,14 The presence of the B, A, and t RFLP alleles (capital letters denote absence of restriction site; small letters presence of restriction site for Bsm I, Apa I, and Taq I RFLPs, respectively) and the relatively short poly-A alleles are highly correlated. These alleles, either alone or in combination, have been associated with increased mRNA expression of the VDR gene, increased serum levels of 1,25-dihydroxy vitamin D, and increased levels of osteocalcin. [15][16][17] The RFLP polymorphisms are most likely not of functional consequence, and the reported associations are probably due to linkage disequilibrium with some 3ЈUTR element, which may or may not be the poly-A repeat. 18 The B and short poly-A alleles have been reported to be protective against the development of colonic adenomas and prostate cancer, respectively. 18 -21 At the start site of the gene, a polymorphism detected with a Fok I digest also has been studied and has been shown to not be in linkage disequilibrium wit...

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

“…Our previous results for rectal cancer suggested a trend towards a protective effect of sunshine exposure in men only. 11 However, the difference could be biological in nature in that Westburg et al have suggested that serum androgen levels in women are regulated by both the AR and estrogen receptor (ER) genes, 28 making a more complicated disease pathway in women than in men. It is also possible that the associations detected are spurious findings; thus other studies to replicate these results are needed.…”

“…Several investigators have studied sunshine exposure independently to better understand the associations between vitamin D and colorectal cancer. [11][12][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.…”

Dairy products, polymorphisms in the vitamin D receptor gene and colorectal adenoma recurrence

“…29,30 In addition, 2 intronic polymorphisms, BsmI and ApaI, and the TaqI polymorphism in exon 9 have been reported to alter VDR expression, probably through linkage disequilibrium with variants in the 3 0 UTR altering VDR-mRNA stability. 31 Epidemiological studies have reported associations between VDR polymorphism genotype and risk of both CRA [32][33][34][35][36] and CRC, [37][38][39] and in some studies, the associations were modified by dietary vitamin D and calcium intakes. [32][33][34][35][36]38,40 Although not a universal finding, 34,39 carriers of variant FokI alleles have been reported to have an increased risk of CRC 40 and advanced CRA 32 which is enhanced in individuals with low calcium intake.…”

“…31 Epidemiological studies have reported associations between VDR polymorphism genotype and risk of both CRA [32][33][34][35][36] and CRC, [37][38][39] and in some studies, the associations were modified by dietary vitamin D and calcium intakes. [32][33][34][35][36]38,40 Although not a universal finding, 34,39 carriers of variant FokI alleles have been reported to have an increased risk of CRC 40 and advanced CRA 32 which is enhanced in individuals with low calcium intake. The homozygous variant BsmI genotype has been found to be associated with a modest protective influence in CRC 38 but not in CRA.…”

“…[32][33][34][35][36]38,40 Although not a universal finding, 34,39 carriers of variant FokI alleles have been reported to have an increased risk of CRC 40 and advanced CRA 32 which is enhanced in individuals with low calcium intake. The homozygous variant BsmI genotype has been found to be associated with a modest protective influence in CRC 38 but not in CRA. 32,33,36 No association between the FokI and TaqI variants and CRA recurrence was reported in one study.…”