Abstract 2196: Genetic correlates of serum 25-hydroxyvitamin D levels and response to vitamin D supplementation.

Abstract

Abstract Epidemiological studies indicate that vitamin D has antineoplastic effects in the colorectum and suggest that vitamin D supplementation may be a promising chemopreventative approach to reduce risk of colorectal cancer. Thus, it is important to consider how genetic factors may modify vitamin D status and response to vitamin D supplementation. We investigated this question among 2,259 participants randomized in the Vitamin D/Calcium Polyp Prevention Study, an on-going, double-blind, placebo-controlled clinical trial of supplementation with vitamin D3 (1000 IU/day) and/or calcium carbonate (1200 mg elemental calcium/day) for the prevention of colorectal adenomas. Candidate single nucleotide polymorphisms (SNPs) were genotyped in or near seven genes involved in vitamin D or calcium metabolism, transport or signaling. Excluding SNPs with MAF<5% and r2>0.8, 23 SNPs were analyzed in vitamin D binding protein (GC), 25-hydroxylase (CYP2R1), 24-hydroxylase (CYP24A1), 1-hydroxylase (CYP27B1), 7-dehydrocholesterol reductase (DHCR7), vitamin D receptor (VDR), and calcium-sensing receptor (CaSR). These included 5 SNPs previously associated with circulating 25-hydroxyvitamin D levels in genome-wide association studies (GWAS): rs2282679, rs12785878, rs3829251, rs10741657 and rs6013897. Linear regression was used to estimate associations with baseline serum 25-hydroxyvitamin D levels and with levels of 25-hydroxyvitamin D achieved after approximately one year of vitamin D supplementation in the trial after adjusting for baseline levels. Analyses were restricted to non-Hispanic white participants (82%) to avoid population stratification and additive genetic models were used. Baseline 25-hydroxyvitamin D was statistically significantly associated with genotype at 3 GWAS hits in GC, DHCR7 and CYP2R1 and at 5 other SNPs in GC, CYP2R1 and CYP24A1. When response to supplementation was investigated, compliance with pill taking was taken into account by restricting analyses to optimally compliant subjects. Genotype at 3 SNPs in VDR, CYP2R1, and CYP24A1 statistically significantly modified the 25-hydroxyvitamin D level achieved with vitamin D supplementation. In conclusion, we have identified variation in or near key vitamin D and calcium pathway genes that modify serum 25-hydroxyvitamin D status and the response to supplementation with vitamin D. This research may identify individuals at risk for poor response to vitamin D supplementation. The public health significance of this work is substantial due to the prevalence of vitamin D insufficiency and the high incidence of colorectal cancer, osteoporosis, and other common diseases associated with poor vitamin D status. Citation Format: Elizabeth L. Barry, Leila A. Mott, Janet L. Peacock, Judith R. Rees, John A. Baron. Genetic correlates of serum 25-hydroxyvitamin D levels and response to vitamin D supplementation. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2196. doi:10.1158/1538-7445.AM2013-2196