Vitamin D deficiency has been associated with bone disease and a host of other major non-skeletal diseases including cardiovascular, infection, cancer and diabetes. Although supplementation may reduce risks, the definitions and cutoffs that establish clinically relevant vitamin D deficiency across racially diverse populations lack consensus. As a public health priority, it is critical to determine who needs to be treated to optimally affect disease outcomes. Blacks consistently have low 25-hydroxy vitamin D (25[OH] D) levels but paradoxically have higher bone mineral density (BMD) and lower osteoporosis risk than whites. Should blacks be treated with vitamin D to prevent osteoporosis? We propose to investigate a novel concept that vitamin D binding protein (VDBP), in the context of the """"""""free hormone hypothesis,"""""""" underlies the physiological mechanisms of this paradox. We recently reported in healthy young adults that VDBP levels: (1) directly correlate with total 25(OH)D levels;(2) inversely correlate with free- and bioavailable-25(OH)D;and, importantly, (3) vary with race. Preliminary data collected by our research team in patients with ESRD and in pregnant women are consistent with these observations. Others have shown that polymorphisms of the VDBP gene exhibit marked racial differences, suggesting that VDBP modulates vitamin D activity. It is therefore likely that all blacks do not have profound free and bioavailable vitamin D deficiency. We plan to determine the influence of circulating VDBP on bioavailable 25(OH) D by comparing stored blood samples from a large (n~2,200) population of black and white subjects enrolled in HANDLS (Healthy Aging in Neighborhoods of Diversity across the Life Span (available at to test the following hypotheses: 1. Blacks have lower levels of VDBP and total 25(OH) D, but similar levels of free and bioavailable 25(OH) D as whites. 2. Free and bioavailable 25(OH)D levels are independently associated with BMD in blacks and whites, inversely and linearly associated with PTH levels, and these associations are stronger than those between total 25(OH)D and BMD.
Our specific aims are to: (1) determine VDBP, total and bioavailable 25(OH)D, and PTH levels;and (2) test for associations between BMD, bioavailable 25(OH)D, and PTH compared to total 25(OH)D.

Public Health Relevance

According to the standard definition, vitamin D deficiency is extremely common in the general population and has been linked with bone disease. Vitamin D, however, circulates in different forms, and this application will determine which specific forms of vitamin D are most strongly linked with bone mineral density in a large population of Blacks and Caucasians in the U.S., and therefore who would be most appropriate to treat for vitamin D deficiency.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
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Special Emphasis Panel (ZRG1)
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Malozowski, Saul N
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Massachusetts General Hospital
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Allegretti, Andrew S; Parada, Xavier Vela; Eneanya, Nwamaka D et al. (2018) Prognosis of Patients with Cirrhosis and AKI Who Initiate RRT. Clin J Am Soc Nephrol 13:16-25
Lim, Kenneth; Hamano, Takayuki; Thadhani, Ravi (2018) Vitamin D and Calcimimetics in Cardiovascular Disease. Semin Nephrol 38:251-266
Berg, Anders H; Bhan, Ishir; Powe, Camille et al. (2017) Acute Homeostatic Changes Following Vitamin D2 Supplementation. J Endocr Soc 1:1135-1149
Nigwekar, Sagar U; Bloch, Donald B; Nazarian, Rosalynn M et al. (2017) Vitamin K-Dependent Carboxylation of Matrix Gla Protein Influences the Risk of Calciphylaxis. J Am Soc Nephrol 28:1717-1722
Bikle, Daniel; Bouillon, Roger; Thadhani, Ravi et al. (2017) Vitamin D metabolites in captivity? Should we measure free or total 25(OH)D to assess vitamin D status? J Steroid Biochem Mol Biol 173:105-116
Nigwekar, Sagar U; Jiramongkolchai, Pawina; Wunderer, Florian et al. (2017) Increased Bone Morphogenetic Protein Signaling in the Cutaneous Vasculature of Patients with Calciphylaxis. Am J Nephrol 46:429-438
Tonelli, Marcello; Karumanchi, S Ananth; Thadhani, Ravi (2016) Epidemiology and Mechanisms of Uremia-Related Cardiovascular Disease. Circulation 133:518-36
Nigwekar, Sagar U; Zhao, Sophia; Wenger, Julia et al. (2016) A Nationally Representative Study of Calcific Uremic Arteriolopathy Risk Factors. J Am Soc Nephrol 27:3421-3429
Zhang, Yanchen; Corapi, Kristin M; Luongo, Maria et al. (2016) Calciphylaxis in peritoneal dialysis patients: a single center cohort study. Int J Nephrol Renovasc Dis 9:235-241
Allegretti, Andrew S; Ortiz, Guillermo; Cui, Jie et al. (2016) Changes in Kidney Function After Transjugular Intrahepatic Portosystemic Shunts Versus Large-Volume Paracentesis in Cirrhosis: A Matched Cohort Analysis. Am J Kidney Dis 68:381-91

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