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

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 (MESA).

Intervention: 2,000 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 y, 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], parathyroid hormone (PTH), and 25-hydroxyvitamin D3 [25(OH)D3].

Results: In genome-wide analyses, SNPs in 8 regions of the genome had significant association (p < 5E-08) with one 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, SNPs within SULT2A1 and CYP24A1 had significant association (p < 0.05 ÷ 36 = 0.0014) with the changes in 1,25(OH)2D3 and PTH, respectively.

Conclusions: Our results reveal potential new pathways of vitamin D regulation that require replication in other vitamin D trials.