Modification of the inverse association between dietary vitamin D intake and colorectal cancer risk by a FokI variant supports a chemoprotective action of Vitamin D intake mediated through VDR binding

Vitamin D has anticarcinogenic properties and might influence colorectal cancer (CRC) risk, but the epidemiological evidence is inconsistent. Many mechanisms of action for vitamin D have been proposed, with some of them initiating via its binding to the vitamin D receptor (VDR). Using a large Scottish case-control study, we investigated (i) main associations between CRC, vitamin D and calcium dietary intake and 4 VDR single nucleotide polymorphisms (rs10735810, rs1544410, rs11568820, rs7975232) and (ii) interaction associations between the VDR variants, vitamin D and calcium intakes. Inverse and dose-dependent associations were found between CRC risk, dietary [Odds ratio (OR) = 0.77, 95% confidence intervals (CI) 0.63, 0.92, p-trend = 0.012] and total vitamin D (OR = 0.80, 95% CI 0.65, 0.98, p-trend = 0.014) intake in multivariable-adjusted logistic regression models, whereas neither calcium intake nor any of the VDR variants were associated with CRC. Additionally, we observed statistically significant interactions (case-control, case-only designs) between vitamin D and calcium intake and rs10735810 (p-interaction 0.02, 0.006, respectively). We conducted meta-analyses of cohort, case-control and serum studies that also showed an inverse association between dietary vitamin D intake and CRC (serum studies: combined OR = 0.70, 95% CI 0.56, 0.87). The evidence of interaction we report here further supports the inverse association between vitamin D mediated through binding to the VDR.