Genetic and Environmental Factors Influencing Circulating Concentration of Vitamin D Metabolites and Odds of Colorectal Neoplasia

Abstract

Circulating concentrations of vitamin D metabolites are associated with risk for a variety of diseases, including colorectal cancer. It is not known what level of circulating 25(OH)D is optimal for health; however, over-the-counter (OTC) vitamin D supplements are commonly used to improve status, though their effectiveness is unknown. It is also not known if polymorphic variation in genes associated with the vitamin D endocrine system is associated with differences in vitamin D metabolite levels or colorectal neoplasia.METHODS: A double-blind, randomized, placebo-controlled trial examined the effect of 400 IU OTC cholecalciferol on circulating concentrations of 25(OH)D. Associations between polymorphic variation in VDR, RXRA, GC, and CASR and circulating vitamin D metabolites or colorectal neoplasia were examined through analysis of the Ursodeoxycholic Acid (UDCA) and Wheat Bran Fiber (WBF) clinical trial data. A single nucleotide polymorphism (SNP) tagging approach was employed and a total of 42 VDR, 32 RXRA, 35 CASR and 25 GC tagSNPs were analyzed.RESULTS: The net change in serum 25(OH)D in the supplement versus placebo group was 2.3 ng/ml (8.5% change, P = 0.06). Principal components analyses revealed gene-level associations between RXRA and serum 1,25(OH)2D concentrations (p = 0.01) as well as GC and 25(OH)D concentrations (p < 0.01). Seven individual GC polymorphisms were significantly associated with circulating measures of 25(OH)D in addition to CASR polymorphism rs1042636 and proximal colorectal neoplasia (p-value =0.02), following a multiple comparisons adjustment. The CART analysis identified rs17467825 as predictive of continuous measures of 25(OH)D. GC polymorphisms rs1555563, rs7041, and rs222029 were identified as significantly predictive of the 25 ng/ml threshold for insufficiency.CONCLUSION: The results demonstrate that daily 400 IU OTC cholecalciferol is sufficient to maintain baseline concentrations of 25(OH)D in healthy adults, but not to significantly increase levels in all individuals. The results also identified polymorphisms in RXRA, GC, and CASR associated with or that predict vitamin D metabolite levels or colorectal neoplasia risk. The results justify further investigation on the optimal vitamin D supplementation dose for the general population and genetic variation that may be related to circulating concentrations of vitamin D metabolites or colorectal neoplasia.