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

Cora M Best; Xiaohui Li; Jerome I Rotter; David K Prince; Simon Hsu; Andrew N Hoofnagle; David Siscovick; Kent D Taylor; Kayleen Williams; Erin D Michos; Bruce M Psaty; Steven Shea; Kenneth M Rice; Karol E Watson; Norrina B Allen; Russell P Tracy; Cassianne Robinson-Cohen; Ian H de Boer; Bryan R Kestenbaum

doi:10.1210/clinem/dgaf025

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

J Clin Endocrinol Metab. 2025 Jan 16:dgaf025. doi: 10.1210/clinem/dgaf025. Online ahead of print.

Authors

Cora M Best^{1

2

3}, Xiaohui Li⁴, Jerome I Rotter⁴, David K Prince¹, Simon Hsu¹, Andrew N Hoofnagle^{1

2}, David Siscovick⁵, Kent D Taylor⁴, Kayleen Williams⁶, Erin D Michos^{7

8}, Bruce M Psaty⁹, Steven Shea^{10

11}, Kenneth M Rice⁶, Karol E Watson¹², Norrina B Allen¹³, Russell P Tracy¹⁴, Cassianne Robinson-Cohen¹⁵, Ian H de Boer¹, Bryan R Kestenbaum¹

Affiliations

¹ Kidney Research Institute, Department of Medicine, University of Washington, Seattle, WA.
² Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA.
³ Food Science and Human Nutrition Department, University of Florida, Gainesville, FL.
⁴ The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA USA.
⁵ New York Academy of Medicine, New York, NY.
⁶ Department of Biostatistics, University of Washington, Seattle, WA.
⁷ Division of Cardiology, Department of Medicine, Johns Hopkins University, Baltimore, MD.
⁸ Department of Epidemiology and the Welch Center for Prevention, Epidemiology and Clinical Research, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD.
⁹ Cardiovascular Health Research Unit, Departments of Medicine, Epidemiology and Health Services, University of Washington, Seattle, WA.
¹⁰ Department of Medicine, Columbia University Vagelos College of Physicians and Surgeons, New York, NY.
¹¹ Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY.
¹² Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA.
¹³ Department of Preventive Medicine, Northwestern University, Chicago, IL.
¹⁴ Department of Biochemistry, University of Vermont, Burlington, VT.
¹⁵ Division of Nephrology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN.

PMID: 39815761
DOI: 10.1210/clinem/dgaf025

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 (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.

Keywords: Clinical Trials; Nutrition; PTH/Vit D/FGF23; Pharmacogenomics.

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