Evidence for alteration of the vitamin D-endocrine system in blacks.

Bell, Norman H.; Greene, Anne S.; Epstein, Sol; Oexmann, Mary Joan; Shaw, Spencer; Shary, Judith

doi:10.1172/jci111995

Cited by 407 publications

(246 citation statements)

References 21 publications

(15 reference statements)

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“…Several studies have shown that black individuals may have higher PTH levels and also larger parathyroid glands than white individuals, and similar findings have been reported among patients with ESRD (15)(16)(17)(18)(19)(20)(21)(22). These findings cannot be entirely explained by differences in calcium intake and vitamin D status, and the possibility that skeletal resistance to PTH may be partly responsible has been suggested (23)(24)(25).…”

Section: Discussionmentioning

confidence: 54%

Screening for Chronic Kidney Disease Complications in US Adults

Ibrahim

Wang

Ishani

et al. 2008

Clinical Journal of the American Society of Nephrology

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Background and objectives: An ideal and effective screening tool should perform equally across ethnic groups. The objective of this study was to determine whether the widely advocated creatinine-based estimated GFR (eGFR) threshold of 60 ml/min per 1.73 m 2 identifies the typical metabolic abnormalities related to chronic kidney disease equally well in minority and nonminority adults.Design, setting, participants, & measurements: This objective was addressed using data for 8918 minority and nonminority adult participants in the National Health and Nutrition Examination Survey 2003 through 2006, which used stratified, multistage, probability sampling methods to assemble a nationwide probability sample of the noninstitutionalized population of the United States. Metabolic abnormalities including BP, potassium, hemoglobin, bicarbonate, uric acid, calcium, phosphorus, and parathyroid hormone were defined by fifth or 95th percentile values.Results: Among participants with eGFR <60 ml/min per 1.73 m 2 , black individuals were more likely than white individuals to have low hemoglobin (adjusted odds ratio [aOR] 3.76; 95% confidence interval [CI] 1.94 to 7.28), elevated uric acid (aOR 2.15; 95% CI 1.26 to 3.68), and elevated parathyroid hormone (aOR 3.93; 95% CI 2.33 to 6.66).Conclusions: Metabolic consequences of reduced eGFR are more common in black individuals and seem to be present at levels well above 60 ml/min per 1.73 m 2 ; thus, black individuals should be screened for the metabolic complications of chronic kidney at higher GFR levels.

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Section: Discussionmentioning

confidence: 54%

Screening for Chronic Kidney Disease Complications in US Adults

Ibrahim

Wang

Ishani

et al. 2008

Clinical Journal of the American Society of Nephrology

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“…Along these lines, it is of possible significance that the vitamin D 25-hydroxylase-deficient subject identified here was Nigerian. Individuals with dark skin require exposure to sunlight for longer periods of time to generate requisite levels of vitamin D 3 as compared with those with less skin pigmentation and may be more sensitive to impaired synthesis of the vitamin (43)(44)(45)(46). Furthermore, we sequenced exon 2 of the CYP2R1 gene in 50 control subjects from Nigeria (22), and identified one individual who was heterozygous for the L99P mutation.…”

Section: -40)mentioning

confidence: 99%

Genetic evidence that the human CYP2R1 enzyme is a key vitamin D 25-hydroxylase

Cheng

Levine

Bell

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

652

399

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The synthesis of bioactive vitamin D requires hydroxylation at the 1␣ and 25 positions by cytochrome P450 enzymes in the kidney and liver, respectively. The mitochondrial enzyme CYP27B1 catalyzes 1␣-hydroxylation in the kidney but the identity of the hepatic 25-hydroxylase has remained unclear for >30 years. We previously identified the microsomal CYP2R1 protein as a potential candidate for the liver vitamin D 25-hydroxylase based on the enzyme's biochemical properties, conservation, and expression pattern. Here, we report a molecular analysis of a patient with low circulating levels of 25-hydroxyvitamin D and classic symptoms of vitamin D deficiency. This individual was found to be homozygous for a transition mutation in exon 2 of the CYP2R1 gene on chromosome 11p15.2. The inherited mutation caused the substitution of a proline for an evolutionarily conserved leucine at amino acid 99 in the CYP2R1 protein and eliminated vitamin D 25-hydroxylase enzyme activity. These data identify CYP2R1 as a biologically relevant vitamin D 25-hydroxylase and reveal the molecular basis of a human genetic disease, selective 25-hydroxyvitamin D deficiency.T he metabolic pathway leading to the synthesis of active vitamin D involves three reactions that occur in different tissues (1). The pathway is initiated in the skin with the UV light-mediated cleavage of 5,7,-cholestadien-3␤-ol to produce the secosteroid (3␤,5Z,7E)-9,10-secocholesta-5,7,10(19)-trien-3-ol (vitamin D 3 ). The second step occurs in the liver and is catalyzed by a cytochrome P450 (CYP) enzyme that hydroxylates carbon 25, producing the intermediate 25-hydroxyvitamin D 3 , which is the major circulatory form of the vitamin. The third and final step takes place in the kidney and involves 1␣-hydroxylation by another CYP, producing 1␣,25-dihydroxyvitamin D 3 . This product is a potent ligand of the vitamin D receptor (VDR) and mediates most of the physiological actions of the vitamin (1).Although the chemical and enzymatic steps in the vitamin D 3 biosynthetic pathway have been known for 30 years (1), the enzyme catalyzing the 25-hydroxylation step in the liver has never been identified. At least six CYPs can catalyze this reaction in vitro, including CYP2C11, CYP2D25, CYP3A4, CYP2J1, CYP27A1, and CYP2R1 (2-4). Of these CYPs, the two most viable candidates for the vitamin D 25-hydroxylase are CYP27A1 and CYP2R1 (2). Both enzymes are expressed in the liver and are conserved among species known to have an active vitamin D signaling pathway. However, mutations in the human and mouse genes encoding the mitochondrial CYP27A1 protein impair bile acid synthesis, but have no consequences for vitamin D metabolism (5-9). It is thus not clear whether the two vitamin D 3 25-hydroxylases represent an example of biological redundancy in an important biosynthetic pathway or whether CYP2R1 alone or some unidentified enzyme fulfills this essential role.In contrast to the uncertainty surrounding vitamin D 3 25-hydroxylase, the renal enzyme responsible for 1␣-hydroxylation of the vitamin...

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“…The key element in our hypothesis is the increased responsiveness of specific target tissues of hypertensive individuals to agonists exerting their cellular effect through the Ca 2+ messenger system and the Na 80 Moreover, hypertensive blacks exhibit a further increase in PTH levels with a high salt intake. 81 These observations suggest that salt sensitivity in blacks may relate to different cellular regulation of Na + and Caj 2+ .…”

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confidence: 99%