{ "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.\n\nObjectives: 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.\n\nMethods: 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.\n\nResults: 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.\n\nDiscussion: 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.", "abstract_shown": true, "affiliations": [ "Food Science and Human Nutrition Department, Institute of Food and Agricultural Sciences, University of Florida", "Kidney Research Institute, Department of Medicine, University of Washington", "ARUP Institute for Clinical and Experimental Pathology, University of Utah", "Department of Pediatrics, Children's Nutrition Research Center USDA/ARS, Baylor College of Medicine", "Division of Cardiology, Department of Medicine, Johns Hopkins University", "Cardiovascular Health Research Unit, Departments of Medicine, Epidemiology and Health Systems and Population Health, University of Washington", "Department of Medicine, Columbia University Vagelos College of Physicians and Surgeons", "The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center", "New York Academy of Medicine", "Department of Preventive Medicine, Northwestern University", "Department of Biochemistry, University of Vermont", "Department of Medicine, David Geffen School of Medicine at UCLA" ], "article_type": null, "arxiv": null, "author_total": 20, "authors": [ { "affs": [ 0 ], "name": "Xinran Hu" }, { "affs": [ 1 ], "name": "Andrew N. Hoofnagle" }, { "affs": [ 1 ], "name": "Simon Hsu" }, { "affs": [ 1 ], "name": "David K. Prince" }, { "affs": [ 2 ], "name": "Mark M. Kushnir" }, { "affs": [ 3 ], "name": "Alexis C. Wood" }, { "affs": [ 3 ], "name": "Stephanie Sisley" }, { "affs": [ 4 ], "name": "Erin D. Michos" }, { "affs": [ 5 ], "name": "Bruce M. Psaty" }, { "affs": [ 6 ], "name": "Steven J. Shea" }, { "affs": [ 7 ], "name": "Jerome I. Rotter" }, { "affs": [ 8 ], "name": "David Siscovick" }, { "affs": [ 9 ], "name": "Norrina B. Allen" }, { "affs": [ 10 ], "name": "Russell P. Tracy" }, { "affs": [ 11 ], "name": "Karol E. Watson" }, { "affs": [ 7 ], "name": "Xiaohui Li" }, { "affs": [ 7 ], "name": "Kent D. Taylor" }, { "affs": [ 1 ], "name": "Bryan R. Kestenbaum" }, { "affs": [ 1 ], "name": "Ian H. de Boer" }, { "affs": [ 0 ], "name": "Cora M. Best" } ], "bibtex": "https://research.draconitic.com/paper/1kagwr32pknpk.bib", "cited_by": 0, "doi": "10.3389/fendo.2026.1910020", "fulltext_url": null, "id": "1kagwr32pknpk", "issns": [ "1664-2392" ], "landing_url": "https://www.frontiersin.org/articles/10.3389/fendo.2026.1910020/full", "language": null, "licence": "CC-BY-4.0", "licence_label": "CC BY 4.0", "licence_source": "article", "licence_url": "https://creativecommons.org/licenses/by/4.0/", "metadata_licence": null, "native_subjects": [], "openalex": null, "pdf_url": null, "pmcid": null, "pmid": null, "published": "2026-10-29", "publisher": "Frontiers Media SA", "ris": "https://research.draconitic.com/paper/1kagwr32pknpk.ris", "sources": [ { "first_seen": "2026-10-30T12:20:20Z", "native_id": "10.3389/fendo.2026.1910020", "source": "crossref", "url": "https://www.frontiersin.org/articles/10.3389/fendo.2026.1910020/full" } ], "subjects": [ { "field": "medicine", "origin": "issn:1664-2392", "subfield": "endocrinology-metabolism" } ], "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", "title_text": "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", "type": "peer-reviewed", "updated_at": "2026-10-31T00:21:09Z", "url": "https://research.draconitic.com/paper/1kagwr32pknpk", "venue": "Frontiers in Endocrinology", "versions": [] }