Abstract 4584: VDR genotype modifies vitamin D efficacy for colorectal adenoma prevention in a randomized controlled trial

Abstract

Abstract Objective: Although epidemiological and pre-clinical research suggests that vitamin D and calcium supplementation reduce colorectal carcinogenesis, we found that they had no effect on risk of colorectal adenoma recurrence in a recently completed randomized controlled trial (Vitamin D/Calcium Polyp Prevention Study, NCT00153816). We now examine whether the effect of supplementation may be modified by common genetic variants in vitamin D and calcium pathway genes previously associated with 25-hydroxyvitamin D levels or other health outcomes. Methods: 41 candidate single nucleotide polymorphisms (SNPs) in 7 genes (GC, DHCR7, CYP2R1, CYP27B1, CYP24A1, VDR and CASR) were genotyped in non-Hispanic white trial participants (N = 1,676). All had at least one adenoma at a baseline colonoscopy and were randomized to treatment with vitamin D3 (1000 IU/day), calcium (1200 mg/day), both or placebo in a modified 2×2 factorial design. Participants were followed until a subsequent colonoscopy 3 or 5 years later and assessed for the presence of at least one adenoma or advanced adenoma (adenoma ≥1 cm, or with >25% villous histology and/or high-grade dysplasia, or cancer). Adjusted risk ratios (RRs) and 95% confidence intervals (CIs) were used to estimate genotype effects, treatment effects and interactions. To account for multiple testing, based on the effective number of independent SNPs, statistical significance was defined as p<0.002. Results: VDR SNP rs731236 (Taq1, minor allele frequency 0.39) statistically significantly modified the effect of vitamin D3 treatment on advanced adenomas (interaction RR = 0.49, 95% CI = 0.31-0.76, P = 0.001) but not on any adenoma (interaction RR = 0.94, 95% CI = 0.80-1.11, P = 0.48). Among participants (N = 249, 15%) with the homozygous variant genotype, the risk of an advanced adenoma was 15.2% among those randomized to placebo, and 3.2% among those randomized to vitamin D; a risk reduction of 78% for vitamin D supplementation (RR = 0.22, 95% CI = 0.08-0.63, P = 0.005). In contrast, among participants with one or more wild type allele (N = 1400, 85%), the risk of an advanced adenoma was 8.8% among those randomized to placebo, and 10.5% among those randomized to vitamin D; an apparent risk increase of 19% for vitamin D supplementation (RR = 1.19, 95% CI = 0.86-1.64, P = 0.3). Several other VDR SNPs in linkage disequilibrium with rs731236 had borderline statistically significant interactions. However, there were only nominally statistically significant (P<0.05) interactions of SNP genotypes with calcium treatment on adenoma outcomes. Conclusions: Our results suggest that the effect of vitamin D3 supplementation on colorectal carcinogenesis depends on common genetic variants in VDR, with a 78% reduction in risk of advanced adenomas in individuals with the rs731236 homozygous variant genotype, and no benefit in individuals with one or more wild type alleles. Note: This abstract was not presented at the meeting. Citation Format: Elizabeth L. Barry, Leila A. Mott, Judith R. Rees, Dennis J. Ahnen, Roberd M. Bostick, Robert S. Bresalier, Douglas J. Robertson, Robert W. Summers, John A. Baron. VDR genotype modifies vitamin D efficacy for colorectal adenoma prevention in a randomized controlled trial. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4584. doi:10.1158/1538-7445.AM2015-4584