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

J Clin Endocrinol Metab. 2014 Oct;99(10):E2133-7. doi: 10.1210/jc.2014-1389. Epub 2014 Jul 29.


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 D3 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 D3 (1000 IU/d), calcium carbonate (1200 mg/d elemental), both, or placebo.

Main outcome measures: Genotype main effects and interactions with vitamin D3 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 D3 treatment and decreased by 1.1 ± 8.4 ng/mL on placebo. The increase in [25(OH)D] due to vitamin D3 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 D3 supplementation may vary according to common genetic differences in vitamin D 25-hydroxylase (CYP2R1), 24-hydroxylase (CYP24A1), and the vitamin D receptor (VDR) genes. These findings have implications for achieving optimal vitamin D status and potentially for vitamin D-related health outcomes.

Trial registration: NCT00153816.

Publication types

  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural

MeSH terms

  • Aged
  • Calcium Carbonate / therapeutic use
  • Cholecalciferol / therapeutic use*
  • Cholestanetriol 26-Monooxygenase / genetics*
  • Cytochrome P450 Family 2
  • Drug Resistance / genetics
  • Female
  • Genetic Variation
  • Genotype
  • Humans
  • Linear Models
  • Male
  • Middle Aged
  • Polymorphism, Single Nucleotide
  • Receptors, Calcitriol / genetics*
  • Treatment Outcome
  • Vitamin D / analogs & derivatives*
  • Vitamin D / blood
  • Vitamin D Deficiency / drug therapy
  • Vitamin D Deficiency / genetics*
  • Vitamin D3 24-Hydroxylase / genetics*


  • Receptors, Calcitriol
  • VDR protein, human
  • Vitamin D
  • Cholecalciferol
  • 25-hydroxyvitamin D
  • Cytochrome P450 Family 2
  • CYP2R1 protein, human
  • Cholestanetriol 26-Monooxygenase
  • CYP24A1 protein, human
  • Vitamin D3 24-Hydroxylase
  • Calcium Carbonate

Associated data