Vitamin D receptor start codon polymorphism and colorectal cancer risk: effect modification by dietary calcium and fat in Singapore Chinese

Abstract

Vitamin D has been implicated as a protective agent against colorectal cancer. We hypothesized that a functional start codon polymorphism in the vitamin D receptor (VDR) influences the risk of colorectal carcinoma. We conducted a case-control study nested within a large cohort of Singapore Chinese. VDR genotypes, determined by FokI restriction endonuclease digestion of PCR-amplified DNA, were performed on 217 colorectal cancer cases and 890 controls. We found that compared with individuals carrying the FF genotype, those with Ff genotype had a 51% increase in risk of colorectal cancer and those with the ff genotype, an 84% increase in risk (P for trend = 0.01). The effect of the VDR genotype on risk appeared to be modified by both dietary calcium and fat. Among those with either low calcium or low fat intake (below the median values in controls), the risk for colorectal cancer increased in a gene-dose-dependent manner such that individuals possessing the ff genotype displayed an approximately 2.5-fold increased risk that was statistically significant. There was little evidence of a VDR genotype-colorectal cancer association among subjects with higher than median values of either dietary fat or calcium.

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

“…Our study also yielded a positive statistical interaction between the occurrence of colon cancer and Fok I polymorphism, which was consistent with the studies carried out by Balcom et al (2008) and Wong et al (2003).…”

“…Fok I polymorphism is known to alter ATG start codon to ACG, that shortens the resulting receptor protein by three amino acid length (Arai et al, 1997;Miyamato et al, 1997;Gross et al, 1998;Jurutka et al, 2000) which is represented by F. This F allele has been repeatedly suggested to transmit stronger anti-proliferative and prodifferentation signals, by interacting with TFIIB (Jurutka et al, 2000;Whitfield et al, 2001;Wong et al, 2003). This observation in our ethnic population is consistent with some of the previous observations found among different races in different parts of the world (Arai et al, 1997;Jurutka et al, 2000).…”

“…Although some attempts have already been made to evaluate the role of Fok I (C/T), VDR polymorphism in various types of cancer, including colorectal cancer (Correa-Cerro et al, 1999;Curran et al, 1999;Ingles 2000;Bretherton-Watt 2001;Chokkalingam 2001;Wong et al, 2003). No such studies directed to unravel the role of Vitamin D and its receptor gene, have been carried out so far in Kashmir valley, which represents the Northern most part of India .…”

“…Till date more than 470 single nucleotide polymorphisms have been discovered on the human VDR gene, most of them are known to have low frequencies (McCullough et al, 2009). Particular stress has been laid on the fact that the VDR transactivation efficiency could potentially be influenced by a polymorphism in start codon as in Fok I region (Wong et al, 2003). It alters an ACG codon that is located ten base pairs upstream from the translation start codon and results in the generation of an additional start codon.…”

Associations between vitamin D, vitamin D receptor gene and the androgen receptor gene with colon and rectal 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. 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.…”