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Peer-reviewedCC BY 4.0Frontiers in Endocrinology

Influence of vitamin D binding protein isoforms on the total and free serum 25-hydroxyvitamin D responses to vitamin D supplementation in older adults in the Multi-Ethnic Study of Atherosclerosis

  • Xinran Hu1
  • Andrew N. Hoofnagle2
  • Simon Hsu2
  • David K. Prince2
  • Mark M. Kushnir3
  • Alexis C. Wood4
  • Stephanie Sisley4
  • Erin D. Michos5
  • Bruce M. Psaty6
  • Steven J. Shea7
  • Jerome I. Rotter8
  • David Siscovick9
8 more authors
  • Norrina B. Allen10
  • Russell P. Tracy11
  • Karol E. Watson12
  • Xiaohui Li8
  • Kent D. Taylor8
  • Bryan R. Kestenbaum2
  • Ian H. de Boer2
  • Cora M. Best1
12 affiliations
  1. 1Food Science and Human Nutrition Department, Institute of Food and Agricultural Sciences, University of Florida
  2. 2Kidney Research Institute, Department of Medicine, University of Washington
  3. 3ARUP Institute for Clinical and Experimental Pathology, University of Utah
  4. 4Department of Pediatrics, Children's Nutrition Research Center USDA/ARS, Baylor College of Medicine
  5. 5Division of Cardiology, Department of Medicine, Johns Hopkins University
  6. 6Cardiovascular Health Research Unit, Departments of Medicine, Epidemiology and Health Systems and Population Health, University of Washington
  7. 7Department of Medicine, Columbia University Vagelos College of Physicians and Surgeons
  8. 8The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center
  9. 9New York Academy of Medicine
  10. 10Department of Preventive Medicine, Northwestern University
  11. 11Department of Biochemistry, University of Vermont
  12. 12Department of Medicine, David Geffen School of Medicine at UCLA
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Abstract

Introduction: Genetic variants that determine the vitamin D binding protein isoform (GC) are consistently associated with total serum 25(OH)D concentration in cross-sectional genome-wide association studies. Previous studies suggest GC isoforms may influence the increment of total 25(OH)D in response to vitamin D supplementation. The free serum 25(OH)D concentration may better reflect vitamin D status, but whether GC isoforms modify the effect of supplementation on free 25(OH)D requires further study.

Objectives: This study aimed to determine the associations between GC isoforms and the increments of total and free 25(OH)D ₃ in response to vitamin D ₃ supplementation among older adults.

Methods: Data were derived from the Multi-Ethnic Study of Atherosclerosis Individualized Response to Vitamin D Treatment (MESA INVITe) Study (NCT02925195). Participants (n = 666) were randomized 3:1 to 16 weeks of 2,000 IU of vitamin D ₃ or placebo daily. Complete data from 559 participants (414 vitamin D ₃ ; 145 placebo) were used for analysis. Total serum 25(OH)D ₃ concentration, GC isoforms, and serum VDBP concentration were determined by LC-MS/MS. Free serum 25(OH)D ₃ was measured by LC-MS/MS following sample preparation by size-exclusion separation. Additionally, an established prediction equation was used to estimate free 25(OH)D ₃ from common biochemical measurements. The associations of GC isoforms with baseline, endpoint, and 16-week changes in total and free 25(OH)D ₃ were modeled with linear regression. Models were adjusted for sex, age, season, body mass index, estimated glomerular filtration rate, and genetic ancestry.

Results: Mean age (SD) of the participants was 72 (8) y; 53% were females, 36% White, 33% Black, 18% Hispanic/Latino, and 13% Chinese. In each treatment group at both baseline and endpoint, total 25(OH)D ₃ was lower among individuals carrying GC2 isoform (3 to 6 ng/mL lower per GC2 allele), whereas free 25(OH)D ₃ , whether measured or calculated, did not vary according to GC isoform. Supplementation significantly increased total and free 25(OH)D ₃ , but the increments of total and free 25(OH)D ₃ were independent of GC isoform.

Discussion: At baseline and endpoint, total serum 25(OH)D ₃ concentration, but not free 25(OH)D ₃ , was lower among individuals with GC2 isoform. However, neither the total nor free 25(OH)D ₃ response to vitamin D ₃ supplementation varied according to GC isoform.

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Cite

BibTeXRIS
BibTeX
@article{hu2026influence,
  title = {{Influence of vitamin D binding protein isoforms on the total and free serum 25-hydroxyvitamin D responses to vitamin D supplementation in older adults in the Multi-Ethnic Study of Atherosclerosis}},
  author = {Xinran Hu and Andrew N. Hoofnagle and Simon Hsu and David K. Prince and Mark M. Kushnir and Alexis C. Wood and Stephanie Sisley and Erin D. Michos and Bruce M. Psaty and Steven J. Shea and Jerome I. Rotter and David Siscovick and Norrina B. Allen and Russell P. Tracy and Karol E. Watson and Xiaohui Li and Kent D. Taylor and Bryan R. Kestenbaum and Ian H. de Boer and Cora M. Best},
  journal = {Frontiers in Endocrinology},
  year = {2026},
  month = oct,
  doi = {10.3389/fendo.2026.1910020},
  url = {https://www.frontiersin.org/articles/10.3389/fendo.2026.1910020/full},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Influence of vitamin D binding protein isoforms on the total and free serum 25-hydroxyvitamin D responses to vitamin D supplementation in older adults in the Multi-Ethnic Study of Atherosclerosis
AU  - Xinran Hu
AU  - Andrew N. Hoofnagle
AU  - Simon Hsu
AU  - David K. Prince
AU  - Mark M. Kushnir
AU  - Alexis C. Wood
AU  - Stephanie Sisley
AU  - Erin D. Michos
AU  - Bruce M. Psaty
AU  - Steven J. Shea
AU  - Jerome I. Rotter
AU  - David Siscovick
AU  - Norrina B. Allen
AU  - Russell P. Tracy
AU  - Karol E. Watson
AU  - Xiaohui Li
AU  - Kent D. Taylor
AU  - Bryan R. Kestenbaum
AU  - Ian H. de Boer
AU  - Cora M. Best
PY  - 2026
DA  - 2026/10/29
JO  - Frontiers in Endocrinology
DO  - 10.3389/fendo.2026.1910020
UR  - https://www.frontiersin.org/articles/10.3389/fendo.2026.1910020/full
AB  - Introduction: Genetic variants that determine the vitamin D binding protein isoform (GC) are consistently associated with total serum 25(OH)D concentration in cross-sectional genome-wide association studies. Previous studies suggest GC isoforms may influence the increment of total 25(OH)D in response to vitamin D supplementation. The free serum 25(OH)D concentration may better reflect vitamin D status, but whether GC isoforms modify the effect of supplementation on free 25(OH)D requires further study.  Objectives: This study aimed to determine the associations between GC isoforms and the increments of total and free 25(OH)D ₃ in response to vitamin D ₃ supplementation among older adults.  Methods: Data were derived from the Multi-Ethnic Study of Atherosclerosis Individualized Response to Vitamin D Treatment (MESA INVITe) Study (NCT02925195). Participants (n = 666) were randomized 3:1 to 16 weeks of 2,000 IU of vitamin D ₃ or placebo daily. Complete data from 559 participants (414 vitamin D ₃ ; 145 placebo) were used for analysis. Total serum 25(OH)D ₃ concentration, GC isoforms, and serum VDBP concentration were determined by LC-MS/MS. Free serum 25(OH)D ₃ was measured by LC-MS/MS following sample preparation by size-exclusion separation. Additionally, an established prediction equation was used to estimate free 25(OH)D ₃ from common biochemical measurements. The associations of GC isoforms with baseline, endpoint, and 16-week changes in total and free 25(OH)D ₃ were modeled with linear regression. Models were adjusted for sex, age, season, body mass index, estimated glomerular filtration rate, and genetic ancestry.  Results: Mean age (SD) of the participants was 72 (8) y; 53% were females, 36% White, 33% Black, 18% Hispanic/Latino, and 13% Chinese. In each treatment group at both baseline and endpoint, total 25(OH)D ₃ was lower among individuals carrying GC2 isoform (3 to 6 ng/mL lower per GC2 allele), whereas free 25(OH)D ₃ , whether measured or calculated, did not vary according to GC isoform. Supplementation significantly increased total and free 25(OH)D ₃ , but the increments of total and free 25(OH)D ₃ were independent of GC isoform.  Discussion: At baseline and endpoint, total serum 25(OH)D ₃ concentration, but not free 25(OH)D ₃ , was lower among individuals with GC2 isoform. However, neither the total nor free 25(OH)D ₃ response to vitamin D ₃ supplementation varied according to GC isoform.
SN  - 1664-2392
ER  -