Genetic Variants Associated With the Biochemical Response to Vitamin D3 in the Multi-Ethnic Study of Atherosclerosis

Abstract

Context: The response to treatment with vitamin D varies between patients. Objective: To identify genetic variants associated with the biochemical response to vitamin D3 supplementation. Design: Randomized placebo-controlled trial conducted between 2017 and 2019. Setting: The trial was nested in an ongoing community-based cohort study, the Multi-Ethnic Study of Atherosclerosis. Intervention: 2000 International Units of vitamin D3 or placebo daily for 16 weeks. Participants: The analytic sample included 427 participants assigned to vitamin D3 (mean age, 73 years; 54% females) and was 36% White, 33% Black, 18% Hispanic, and 14% Chinese. Main Outcome Measures: The biochemical response to vitamin D3 included changes in serum concentrations of 1,25-dihydroxyvitamin D3 [1,25(OH)2D3], PTH, and 25-hydroxyvitamin D3 [25(OH)D3]. Results: In genome-wide analyses, single nucleotide polymorphisms in 8 regions of the genome had significant association (P < 5E-08) with 1 of the traits (2 with change in 1,25(OH)2D3, 1 with change in PTH, and 5 with change in 25(OH)D3). rs16867276 within an intergenic region on 2q31 was associated with change in serum 1,25(OH)2D3 (+8.37 pg/mL difference per effect allele; P = 4.93E-08) and was the only locus that achieved genome-wide significance in transethnic meta-analysis. rs114044709 adjacent to FAM20A, which encodes a protein required for biomineralization, was associated with change in PTH among Black participants (+20.32 pg/mL difference per effect allele; P = 1.34E-08). In candidate analyses, single nucleotide polymorphisms within SULT2A1 and CYP24A1 had significant association (P < .05÷36 = .0014) with the changes in 1,25(OH)2D3 and PTH, respectively. Conclusion: Our results reveal potential new pathways of vitamin D regulation that require replication in other vitamin D trials.