Epidemiological studies have suggested a reduced risk of several cancers associated with an adequate vitamin D (VD) status. Previous meta-analyses evaluating serum vitamin D and cancer risk showed a consistent inverse relationship between serum 25-hydroxyvitamin D levels and colorectal cancer. Single nucleotide polymorphisms (SNPs) of the vitamin D receptor (VDR) are important regulators of the vitamin D pathway and they may indirectly modulate cancer risk. Several studies have investigated VDR SNPs, but the results on their associations with cancer risk are controversial. We carried a meta-analysis to investigate the association of the major VDR SNPs with colorectal cancer risk (CRC).
A systematic literature search was performed following a pre-defined protocol and using validated search strategies up to April 2014. This meta-analysis shows the summary odd ratio (SOR) overall and by ethnicity, obtained with random effect models and investigating heterogeneity.
The meta-analysis included for BsmI 13 studies with 8,709 and 10,010 controls, for FokI 16 studies with 8,877 cases and 10,548 controls, and for ApaI, Cdx2 or TaqI 10 studies with 6,443 cases and 6,915 controls.
We found a significant increased risk between the TaqI tt genotype and CRC: SOR= 1.43 (95%CI: 1.30-1.58), evaluating eight studies. Moreover we found similar results for non Caucasians (SOR= 1.47; 95%CI: 1.28-1.7). Furthermore BsmI showed a significant risk reduction (SOR=0.89; 95%CI: 0.80-0.98) for BB genotype versus bb and borderline significant for Bb vs bb (SOR=0.94; 95%CI: 0.87-1.01).
FokI, ApaI and Cdx2 polymorphisms did not show any significant association for CRC. For FokI we estimated a SOR=1.05 (95%CI: 0.84-1.31) for ff vs FF genotype. Five studies evaluated ApaI and Cdx2 with SOR=1.21 (95%CI: 0.82-1.78) and SOR=1.24 (95%CI: 0.94-1.63), respectively for ApaI aa vs AA, and Cdx2 gg vs GG.
We also found a significant 6-7% reduction of cancer risk at any site respectively for carriers of Bb genotype (SOR= 0.94; 95%CI: 0.90-0.99) and for carriers of BsmI BB genotype (SOR; 95%CI: 0.93; 0.89-0.98) compared to bb carriers.
BsmI B allele has a very wide range from 0.5% to 46% (with a outlier deviating from Hardy-Weinberg equilibrium up to 74%). FokI f allele was from 25% to 48%, among control subjects and for three studies, a significant departure from Hardy-Weinberg equilibrium was observed. The TaqI t allele frequency is relatively broad ranging from 4% to 41%. Interestingly in Asian populations the t allele appear to be quite rare and several studies did not present homozygote tt carriers but only subjects with tT genotype. ApaI a allele frequency ranges from 23% to 50%. Cdx2 g in Caucasian and Asian populations ranges from 21% to 34%; interestingly in a study, evaluating the risk for other cancer site in African-American, the a allele ranges from 73% to 79%.
No indication of publication bias was found.
In conclusion, in our meta-analysis TaqI tt genotype showed an increased risk for colorectal cancer. BsmI might affect VD activities especially in Caucasians. FokI, ApaI and Cdx2 SNPs did not show a significant cancer risk association. A differential effect due to ethnicity is suggested. The VDR genotype might become more relevantly clustered in specific haplotype, for specific tumor biology, subjects characteristics or with other genes involved in the vitamin D metabolisms, especially for VD binding protein.
Citation Format: Sara Gandini, Patrizia Gnagnarella, Sara Raimondi, Elena Tagliabue, Davide Disalvatore, Davide Serrano. Meta-analysis on vitamin D Receptor polymorphisms and colorectal cancer risk. [abstract]. In: Proceedings of the Thirteenth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2014 Sep 27-Oct 1; New Orleans, LA. Philadelphia (PA): AACR; Can Prev Res 2015;8(10 Suppl): Abstract nr A39.