Effect of genetic factors on the response to vitamin D3 supplementation in the VIDARIS randomised controlled trial

Abstract Objectives : Supplementation provides the best means of improving vitamin D status but individual responses vary, which is partly genetically determined. We examined whether 28 single nucleotide polymorphisms in six key vitamin D pathway genes (GC, DHCR7, CYP2R1, CYP24A1, CYP27B1, VDR) were associated with differences in response to supplementation. Methods/Subjects : Participants (n=313; n= 160 vitamin D, n= 153 placebo) were part of the Vitamin D and Acute Respiratory Infections Study (VIDARIS), a double-blind, randomized, controlled trial involving oral monthly supplementation of either vitamin D3 (200,000IU each of the first two months, thereafter 100,000IU monthly) or placebo for 18 months. Circulating 25OHD concentrations at baseline, 2, 6, 12 and 18 months, and vitamin D binding protein (Gc-globulin) and calculated free 25OHD concentrations at baseline and two months were obtained. Multiple regression was used to model associations between genetic variants and 25OHD, Gc-globulin and free 25OHD concentrations. Results : SNPs within GC, CYP2R1 and CYP27B1 were associated with 25OHD concentrations following supplementation. However, only two GC gene SNPs (rs2282679, rs1155563) were significant after adjustment for multiple testing. This effect disappeared after more than two months of supplementation. None of the SNPs were significantly associated with Gc-globulin concentrations, however there was a significant interaction with one SNP in DHCR7 (rs12785878), which was associated with reduced free 25OHD concentrations in the supplemented arm. Conclusion : Only variants of GC were associated with 25OHD concentrations following supplementation. This effect was modest and disappeared after more than two months of supplementation, suggesting it may be time/dose-dependent and saturable.