Genetic Variants in CYP2R1, CYP24A1, and VDR Modify the Efficacy of Vitamin D3 Supplementation for Increasing Serum 25-Hydroxyvitamin D Levels in a Randomized Controlled Trial

Context: Adequate serum 25-hydroxyvitamin D concentrations, [25(OH) D], are required for optimal bone health, and low levels are associated with chronic diseases. Objective: We investigated whether 41 candidate single nucleotide polymorphisms (SNPs) in vitamin D and calcium pathway genes (GC, DHCR7, CYP2R1, CYP27B1, CYP24A1, VDR, and CASR) are associated with [25(OH) D] or modify the increase in [25(OH) D] from vitamin D-3 supplementation. Design and Setting: Baseline and year 1 [25(OH)D] measurements from a randomized controlled trial conducted at 11 clinical centers in the United States. Participants: A total of 1787 healthy non-Hispanic white participants aged 45-75 years. Interventions: Vitamin D-3 (1000 IU/d), calcium carbonate (1200 mg/d elemental), both, or placebo. Main Outcome Measures: Genotype main effects and interactions with vitamin D-3 treatment estimated using multiple linear regression. Results: The baseline serum [25(OH)D] was 25.4 +/- 8.7 ng/mL (mean +/- SD). Associations with baseline levels were discovered for SNPs in CYP24A1 (rs2209314, rs2762939) and confirmed for SNPs in GC and CYP2R1. After 1 year, [25(OH)D] increased on average by 6.1 +/- 8.9 ng/mL on vitamin D-3 treatment and decreased by 1.1 +/- 8.4 ng/mL on placebo. The increase in [25(OH)D] due to vitamin D-3 supplementation was modified by genotypes at rs10766197 near CYP2R1, rs6013897 near CYP24A1, and rs7968585 near VDR. Conclusions: The increase in [25(OH)D] attributable to vitamin D-3 supplementation may vary according to common genetic differences in vitamin D 25-hydroxylase (CYP2R1), 24-hydroxylase (CYP24A1), and the vitamin Dreceptor(VDR) genes. These findings have implications for achieving optimal vitamin D status and potentially for vitamin D-related health outcomes.