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Cited by 163Vitamin D Research StudiesBone health and osteoporosis researchRace, Genetics, and Society

Free 25-Hydroxyvitamin D: Impact of Vitamin D Binding Protein Assays on Racial-Genotypic Associations

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Nielson, Carrie M., Jones, Kerry S., Chun, Rene F., Jacobs, Jon M., Wang, Ying, Hewison, Martin, Adams, John S., Swanson, Christine M. +15 more·2016·The Journal of Clinical Endocrinology & Metabolism
DOI 10.1210/jc.2016-1104PMC PMC4870848
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Abstract

CONTEXT: Total 25-hydroxyvitamin D (25OHD) is a marker of vitamin D status and is lower in African Americans than in whites. Whether this difference holds for free 25OHOD (f25OHD) is unclear, considering reported genetic-racial differences in vitamin D binding protein (DBP) used to calculate f25OHD. OBJECTIVES: Our objective was to assess racial-geographic differences in f25OHD and to understand inconsistencies in racial associations with DBP and calculated f25OHD. DESIGN: This study used a cross-sectional design. SETTING: The general community in the United States, United Kingdom, and The Gambia were included in this study. PARTICIPANTS: Men in Osteoporotic Fractures in Men and Medical Research Council studies (N = 1057) were included. EXPOSURES: Total 25OHD concentration, race, and DBP (GC) genotype exposures were included. OUTCOME MEASURES: Directly measured f25OHD, DBP assessed by proteomics, monoclonal and polyclonal immunoassays, and calculated f25OHD were the outcome measures. RESULTS: Total 25OHD correlated strongly with directly measured f25OHD (Spearman r = 0.84). Measured by monoclonal assay, mean DBP in African-ancestry subjects was approximately 50% lower than in whites, whereas DBP measured by polyclonal DBP antibodies or proteomic methods was not lower in African-ancestry. Calculated f25OHD (using polyclonal DBP assays) correlated strongly with directly measured f25OHD (r = 0.80-0.83). Free 25OHD, measured or calculated from polyclonal DBP assays, reflected total 25OHD concentration irrespective of race and was lower in African Americans than in US whites. CONCLUSIONS: Previously reported racial differences in DBP concentration are likely from monoclonal assay bias, as there was no racial difference in DBP concentration by other methods. This confirms the poor vitamin D status of many African-Americans and the utility of total 25OHD in assessing vitamin D in the general population.

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  • No racial difference in DBP was observed when using a polyclonal assay or applying LC-MS/MS, so the earlier conclusion was most likely the result of a monoclonal assay bias, confirming poor vitamin D status in subjects of African origin.

    “However, as no racial difference in DBP was observed when using a polyclonal assay or applying LC–MS/MS, this conclusion was most likely the result of a monoclonal assay bias, confirming poor vitamin D status in subjects of African origin [81, 82].”

    From Role of sex hormone-binding globulin in the free hormone hypothesis and the relevance of free testosterone in androgen physiology (2022) · cites this paper as [81]

    The Results report that DBP was not lower in African-ancestry participants when measured with polyclonal assays or proteomic methods; the Discussion attributes the earlier finding to monoclonal-assay bias. The paper finds lower free and total 25OHD in African Americans than in US whites, but the claim extends poor vitamin D status to people of African origin generally. The Results instead report higher total 25OHD in Gambians than in UK whites. (LLM, conf=0.87)

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  1. [1]Institute of Medicine. 2011 Dietary reference intakes for calcium and vitamin D. Washington, DC: The National Academies Press. 21796828
  2. [2]Rosen CJ Adams JS Bikle DD The nonskeletal effects of vitamin D: an Endocrine Society scientific statement. Endocr Rev. 2012; 33: 456– 492. 22596255 PMC3365859
  3. [3]Chun RF Peercy BE Orwoll ES Nielson CM Adams JS Hewison M Vitamin D and DBP: the free hormone hypothesis revisited. J Steroid Biochem Mol Biol. 2014; 144 Pt A: 132– 137. 24095930 PMC3976473
  4. [4]Johnsen MS Grimnes G Figenschau Y Torjesen PA Almas B Jorde R Serum free and bio-available 25-hydroxyvitamin D correlate better with bone density than serum total 25-hydroxyvitamin D. Scand J Clin Lab Invest. 2014; 74: 177– 183. 24383929
  5. [5]Bhan I Powe CE Berg AH Bioavailable vitamin D is more tightly linked to mineral metabolism than total vitamin D in incident hemodialysis patients. Kidney Int. 2012; 82: 84– 89. 22398410 PMC3376220
  6. [6]Powe CE Ricciardi C Berg AH Vitamin D-binding protein modifies the vitamin D-bone mineral density relationship. J Bone Miner Res. 2011; 26: 1609– 1616. 21416506 PMC3351032
  7. [7]Ashraf AP Alvarez JA Dudenbostel T Associations between vascular health indices and serum total, free and bioavailable 25-hydroxyvitamin D in adolescents. PLoS ONE. 2014; 9: e114689. 25479358 PMC4257727
  8. [8]Jemielita TO Leonard MB Baker J Association of 25-hydroxyvitamin D with areal and volumetric measures of bone mineral density and parathyroid hormone: impact of vitamin D-binding protein and its assays. Osteoporos Int. 2016; 27: 617– 626. 26359185 PMC4924926
  9. [9]LeFevre ML Screening for vitamin D deficiency in adults: U.S. Preventive services task force recommendation statement. Ann Intern Med. 2015; 162: 133– 140. 25419853
  10. [10]Bouillon R Van Assche FA Van Baelen H Heyns W De Moor P Influence of the vitamin D-binding protein on the serum concentration of 1,25-dihydroxyvitamin D3: significance of the free 1,25-dihydroxyvitamin D3 concentration. J Clin Invest. 1981; 67: 589– 596. 6894152 PMC370606
  11. [11]Chun RF Peercy BE Adams JS Hewison M Vitamin D binding protein and monocyte response to 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D: analysis by mathematical modeling. PLoS One. 2012; 7: e30773. 22292037 PMC3265504
  12. [12]Kambou MI Ferrell RE Ethnic variation in vitamin D-binding protein (GC): a review of isoelectric focusing studies in human populations. Hum Genet. 1986; 72: 281– 293. 3516862
  13. [13]Powe CE Evans MK Wenger J Vitamin D-binding protein and vitamin D status of black Americans and white Americans. N Engl J Med. 2013; 369: 1991– 2000. 24256378 PMC4030388
  14. [14]Hannan MT Litman HJ Araujo AB Serum 25-hydroxyvitamin D and bone mineral density in a racially and ethnically diverse group of men. J Clin Endocrinol Metab. 2008; 93: 40– 46. 17986641 PMC2190744
  15. [15]Looker AC Pfeiffer CM Lacher DA Schleicher RL Picciano MF Yetley EA Serum 25-hydroxyvitamin D status of the US population: 1988–1994 compared with 2000–2004. Am J Clin Nutr. 2008; 88: 1519– 1527. 19064511 PMC2745830
  16. [16]Bhan I Vitamin D binding protein and bone health. Int J Endocrinol. 2014; 2014: 561214. 24987416 PMC4058579
  17. [17]Durazo-Arvizu RA Camacho P Bovet P 25-Hydroxyvitamin D in African-origin populations at varying latitudes challenges the construct of a physiologic norm. Am J Clin Nutr. 2014; 100: 908– 914. 25008852 PMC4135499
  18. [18]Bouillon R Baelen HV Moor PD The measurement of the vitamin D-binding protein in human serum. J Clin Endocrinol Metab. 1977; 45: 225– 231. 885987
  19. [19]Jones KS Assar S Harnpanich D 25(OH)D2 half-life is shorter than 25(OH)D3 half-life and is influenced by DBP concentration and genotype. J Clin Endocrinol Metab. 2014; 99: 3373– 3381. 24885631 PMC4207933
  20. [20]Winters SJ Chennubhatla R Wang C Miller JJ Influence of obesity on vitamin D-binding protein and 25-hydroxy vitamin D levels in African American and white women. Metabolism. 2009; 58: 438– 442. 19303961
  21. [21]Henderson CM Lutsey PL Misialek JR Measurement by a novel LC-MS/MS methodology reveals similar serum concentrations of vitamin d-binding protein in blacks and whites. Clin Chem. 2016; 62: 179– 187. 26453697 PMC4698095
  22. [22]Bouillon R Jones K Schoenmakers I Vitamin D-binding protein and vitamin D in Blacks and Whites. N Engl J Med. 2014; 370: 879. 24571765
  23. [23]Hollis BW Bikle DD Vitamin D-binding protein and vitamin D in blacks and whites. N Engl J Med. 2014; 370: 879– 880. 24571766 PMC4165606
  24. [24]Orwoll E Blank JB Barrett-Connor E Design and baseline characteristics of the osteoporotic fractures in men (MrOS) study–a large observational study of the determinants of fracture in older men. Contemp Clin Trials. 2005; 26: 569– 585. 16084776
  25. [25]Singh RJ Taylor RL Reddy GS Grebe SKG C-3 epimers can account for a significant proportion of total circulating 25-Hydroxyvitamin D in infants, complicating accurate measurement and interpretation of vitamin D status. J Clin Endocrinol Metab. 2006; 91: 3055– 3061. 16720650
  26. [26]Casetta B Jans I Billen J Vanderschueren D Bouillon R Development of a method for the quantification of 1α,25(OH)2-vitamin D3 in serum by liquid chromatography tandem mass spectrometry without derivatization. Eur J Mass Spectrom. 2010; 16: 81– 89. 20065517
  27. [27]Schwartz JB Lai J Lizaola B A comparison of measured and calculated free 25(OH) vitamin D levels in clinical populations. J Clin Endocrinol Metab. 2014; 99: 1631– 1637. 24483159 PMC4010704
  28. [28]Schwartz JB Lai J Lizaola B Variability in free 25(OH) vitamin D levels in clinical populations. J Steroid Biochem Mol Biol. 2014; 144 Pt A: 156– 158. 24240067 PMC4022715
  29. [30]Murphy AB Nyame Y Martin IK Vitamin D deficiency predicts prostate biopsy outcomes. Clin Cancer Res. 2014; 20: 2289– 2299. 24789033 PMC4104275
  30. [31]Fiscella K Franks P Vitamin D, race, and cardiovascular mortality: findings from a national US sample. Ann Fam Med. 2010; 8: 11– 18. 20065273 PMC2807382
  31. [32]Ponda MP McGee D Breslow JL Vitamin D-binding protein levels do not influence the effect of vitamin D repletion on serum PTH and calcium: data from a randomized, controlled trial. J Clin Endocrinol Metab. 2014; 99: 2494– 2499. 24712573 PMC4079311
  32. [33]Aloia J Mikhail M Dhaliwal R Free 25(OH)D and the vitamin D paradox in African Americans. J Clin Endocrinol Metab. 2015; 100: 3356– 3363. 26161453 PMC4570168
  33. [34]Bouillon R van Baelen H de Moor P Comparative study of the affinity of the serum vitamin D-binding protein. J Steroid Biochem. 1980; 13: 1029– 1034. 6893475
  34. [35]Boutin B Galbraith RM Arnaud P Comparative affinity of the major genetic variants of human group-specific component (vitamin D-binding protein) for 25-(OH) vitamin D. J Steroid Biochem. 1989; 32: 59– 63. 2913402
  35. [36]Kawakami M Imawari M Goodman DS Quantitative studies of the interaction of cholecalciferol ((vitamin D3) and its metabolites with different genetic variants of the serum binding protein for these sterols. Biochem J. 1979; 179: 413– 423. 90502 PMC1186639
  36. [37]Arnaud J Constans J Affinity differences for vitamin D metabolites associated with the genetic isoforms of the human serum carrier protein (DBP). Hum Genet. 1993; 92: 183– 188. 8370586
  37. [38]Redmond J Jarjou LM Zhou B Prentice A Schoenmakers I Ethnic differences in calcium, phosphate and bone metabolism. Proc Nutr Soc. 2014; 73: 340– 351. 24621477 PMC3981475
  38. [39]Bartalena L Robbins J Variations in thyroid hormone transport proteins and their clinical implications. Thyroid. 1992; 2: 237– 245. 1422238
  39. [40]Bikle DD Gee E Halloran B Haddad JG Free 1,25-dihydroxyvitamin D levels in serum from normal subjects, pregnant subjects, and subjects with liver disease. J Clin Invest. 1984; 74: 1966– 1971. 6549014 PMC425383

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Authors
Nielson, C. M., Jones, K. S., Chun, R. F., Jacobs, J. M., Wang, Y., Hewison, M., Adams, J. S., Swanson, C. M., Lee, C. G., Vanderschueren, D., Pauwels, S., Prentice, A., Smith, R. D., Shi, T., Gao, Y., Schepmoes, A. A., Zmuda, J. M., Lapidus, J., Cauley, J. A., Bouillon, R., Schoenmakers, I., Orwoll, E. S., & for the Osteoporotic Fractures in Men (MrOS) Research Group
Affiliations
Pacific Northwest National Laboratory (US)
Corresponding author
Bouillon, Roger
ORCID
Venue
The Journal of Clinical Endocrinology & Metabolism
Publisher
The Endocrine Society
Published
2016-05
Volume
101
Issue
5
Pages
2226-2234
ISSN
  • 0021-972X (ISSN-L)
  • 1945-7197
DOI
10.1210/jc.2016-1104
PMC
PMC4870848
OpenAlex
W2303177741
Cited by
163
References
0
Citations by year
2026: 4 · 2025: 5 · 2024: 8 · 2023: 13 · 2022: 7 · 2021: 10 · 2020: 17 · 2019: 26 · 2018: 26 · 2017: 34 · 2016: 13
FWCI
30.00
Type
journal article
Language
en
Open access
Licence
cc-by-nc
Locations
  • The Journal of Clinical Endocrinology & Metabolism (publishedVersion, cc-by-nc)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • University of Birmingham Research Portal (University of Birmingham) (publishedVersion, cc-by-nc)
  • Lirias (submittedVersion, other-oa)
  • UEA Digital Repository (University of East Anglia) (submittedVersion)
Funders
  • U.S. Department of Energy (DE-AC05–76RL01830, DE-AC05?, DE-AC05-76RL0)
  • Battelle (DE- AC05-76RL01830, DE-AC05)
  • Department for International Development (MCA760‐5QX00, U105960371, U123261351)
  • Fonds Wetenschappelijk Onderzoek (G. 0858.11)
  • KU Leuven (GOA 15/0/01)
  • Vlaamse regering
  • National Institutes of Health (UL1TR000128, UL1TR000124, 5p41gm103493-20, AG042139, AR066160, AG042140, AG027810, P41-GM103493, TR000128, AG042124, AG042143, AG042145, DE-AC05-76RL01830)
  • Medical Research Council (MC-A760–5QX00, U105960371, U123261351)
  • National Institute on Aging (U01AG042145, U01AG042168, AG042140, AG042139, U01AG042143, U01AG027810, AG042124, U01AG042139, U01AG042124, AG027810, U01AG042140, AG042143)
  • National Institute of General Medical Sciences (P41-GM103493)
  • National Institute of Diabetes and Digestive and Kidney Diseases (T32DK007674)
  • National Institute of Arthritis and Musculoskeletal and Skin Diseases (AR063910, U01AR066160, AR066160, P50AR063020, K01AR062655, R01AR063910)
  • National Center for Advancing Translational Sciences (TR000128)
  • Pacific Northwest National Laboratory (DEAC0576RL01830)
Topics
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Vitamin D Research Studies
  • Health Sciences › Medicine › Orthopedics and Sports Medicine › Bone health and osteoporosis research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Race, Genetics, and Society
Keywords
free 25-hydroxyvitamin D, vitamin D binding protein, racial differences, African Americans, vitamin D status, GC gene polymorphisms, vitamin D deficiency
MeSH terms
Adult, Aged, Black or African American, Cross-Sectional Studies, Humans, Male, Vitamin D, Vitamin D-Binding Protein, Black People, White People

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