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

Abstract

Vitamin D receptor (VDR) activation inhibits proliferation and angiogenesis in the colorectal epithelium, and inhibits metastasis of colorectal tumors. Polymorphisms in the VDR gene alter receptor cellular levels and functioning, and may confer altered susceptibility to colorectal neoplasia. We aimed to investigate the influence of VDR polymorphisms and dietary factors impacting on vitamin D metabolism on colorectal adenoma (CRA) recurrence. Data on dietary intakes of calcium, vitamin D and dairy products were collected from 853 participants in the United Kingdom Colorectal Adenoma Prevention trial, a randomized trial of aspirin and folate for CRA recurrence prevention. The VDR Cdx2, FokI, BsmI, ApaI and TaqI polymorphisms were genotyped in 546 participants with available DNA, and gene-diet interaction analyses performed in 480. Dairy product intake was inversely related to CRA recurrence risk independent of calcium and vitamin D [relative risk (RR) 5 0.64; 95% confidence intervals (CIs): 0.47-0.88, for subjects in the highest compared to lowest intake tertile, p trend 5 0.005]. Milk accounted for 60% of dairy product intake, and on analysis of milk and nonmilk dairy products separately recurrence risk in individuals in the highest tertile of milk intake was half that of lowest tertile individuals (RR 5 0.52; 95% CI: 0.38-0.72, p trend 5 3.2 3 10 25 ), whereas nonmilk dairy products did not influence recurrence. VDR polymorphism genotypes and haplotypes did not directly alter recurrence risk, but the reduction in risk associated with high dairy product intake was confined to individuals with ApaI aA/AA genotype (p interaction 5 0.02). These findings indicate dairy products, and in particular milk, have chemopreventive activity against CRA recurrence. ' 2008 Wiley-Liss, Inc.Key words: colorectal adenoma recurrence; dairy products; VDR; polymorphism Colorectal cancer (CRC) is the third commonest cancer worldwide after lung and breast cancer, and two-thirds of CRC occurs in developed countries. 1 Up to 90% of CRCs develop from colorectal adenomas (CRAs) and colonoscopic removal of CRA reduces the incidence of CRC. 2,3 In some individuals, the recurrence rate for CRA is as high as 40-50% after 3 years, 4 CRA recurrence is a surrogate marker for CRC risk and prevention of CRA recurrence is a useful endpoint for evaluating chemopreventive agents. 5 Activation of vitamin D receptors (VDRs) present in many cell types, including colorectal epithelial cells, can inhibit proliferation, angiogenesis and invasiveness, and studies in animal models indicate that vitamin D supplementation can lower the incidence and metastatic potential of intestinal tumors. 6-9 Ecological studies correlating sunlight exposure with cancer incidence provided the first evidence that vitamin D levels are inversely related to CRC development in humans. 10 Subsequent epidemiological studies have reported lower risks of CRA and CRC in individuals with high intakes and circulating levels of vitamin D. 11-14 Vitamin D plays a crucial role in calcium me...

Vitamin D Receptor and Calcium Sensing Receptor Polymorphisms and the Risk of Colorectal Cancer in European Populations

“…Results from studies on adenomas and CRC primarily indicate either no association or a reduced risk for the B allele of the VDR BsmI (13-15, 20). Similarly, previous findings for the f allele of the VDR Fok1 are either null (15,(17)(18)(19) lyzed here is intronic and is in strong linkage disequilibrium with the poly(A) sequence in the 3′ untranslated region whose length may determine mRNA stability and hence affect local VDR protein levels (19,38). But it is not clear whether in fact the BsmI allele has an effect on the expression level or activity of the translated VDR protein (12).…”

“…However, in other studies, an effect modification has been observed with lower dietary intake levels of either calcium, vitamin D, or dairy products leading to reduced risk of colorectal adenomas with the BB genotype of the BsmI (14), the ff genotype of the Fok1 (13), or the aA/AA genotype of the ApaI VDR genotypes (15). Considering cancer end points, studies on North American populations suggest that the BsmI BB or PolyA SS VDR genotypes may be associated with a reduced risk of cancer in the colon (19) and possibly in the rectum (20).…”

“…With respect to colorectal adenomas, epidemiologic studies conducted primarily in North American populations have shown no associations for the BsmI (13-15), TaqI (15)(16)(17), FokI (15,17,18), or other VDR genotypes (15). However, in other studies, an effect modification has been observed with lower dietary intake levels of either calcium, vitamin D, or dairy products leading to reduced risk of colorectal adenomas with the BB genotype of the BsmI (14), the ff genotype of the Fok1 (13), or the aA/AA genotype of the ApaI VDR genotypes (15).…”

Association of a VDR Gene Polymorphism with Risk of Colorectal Cancer in Kashmir

“…If the initiating translation starts from this alternative site (thymine variant), it results in the generation of a longer VDR protein of 427 amino acids (Kostner et al, 2009). The polymorphisms in this area have been studied singly and in combination with other polymorphisms of VDR in a number of malignant and non malignant conditions (Chiu et al, 2001;Malecki et al, 2003;Park et al, 2006;Kadyska et al, 2007;Hubner et al, 2008;Neyestani et al, 2013).…”

New insights into calcium, dairy and colon cancer

“…It is known that such polymorphisms are functionally associated with differences in bone density and in serum calcitriol levels, but whether they affect the action of vitamin D upon the colon is unclear [27] . However, high dairy intake effects upon colon adenoma recurrence has been restricted to individuals with the Apal aA/AA genotype [28] . One small, but unique study has described the effects of 6 mo supplemental calcium (1200 mg) plus vitamin D (400 IU) to subjects with adenomatous polyps which were transected with one half tattooed and left in situ.…”