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      Vitamin D Receptor Gene Polymorphism Detected by Digestion with Apa I Influences the Parathyroid Response to Extracellular Calcium in Japanese Chronic Dialysis Patients

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          Background: To play its physiological role, 1,25(OH)<sub>2</sub>D<sub>3</sub> must bind to a specific vitamin D receptor (VDR) in the nucleus. We have previously reported that VDR gene polymorphism influences the parathyroid function in patients with end-stage renal disease (ESRD). In the present study, we have investigated the relationship between the parathyroid responsiveness and VDR gene polymorphism, as detected by the Apa I restriction enzyme, by changing the concentration of Ca<sup>2+</sup> in the dialysate. Methods: 58 Japanese ESRD patients undergoing renal replacement therapy in our institution were evaluated. Genomic DNA was extracted from peripheral leukocytes and digested at the intron between exon 8 and exon 9 of the VDR gene using Apa I enzyme. Then alleles were classified into genotype A (undigested allele) and genotype a (digested allele). Extracellular ionized calcium ([Ca<sup>2+</sup>]<sub>e</sub>), serum phosphate, and intact parathyroid hormone (PTH) were measured before and after each hemodialysis (HD) session with dialysates having different concentrations of Ca<sup>2+</sup> (1.5 or 1.25 mmol/l). The significance of differences in statistical analyses was defined within confidence limits of 5.0%. Results: The AA, Aa, and aa genotypes were observed in 7/58 patients (12.1%), 23/58 patients (39.6%), and 28/58 patients (48.3%), respectively. The PTH reduction after HD with the 1.5-mmol/l Ca dialysate did not differ significantly between group AA+Aa and group aa. On the other hand, the PTH increase was significantly higher in group aa than in group AA+Aa after HD with the 1.25-mmol/l Ca dialysate (p = 0.0107), despite a similar PTH level before HD. Similarly, the percent increase of PTH after HD with the 1.25-mmol/l Ca dialysate was significantly higher (p = 0.0112) in group aa (50.2 ± 9.4%) than in group AA+Aa (19.7 ± 7.2%). There were no significant differences between the two groups in [Ca<sup>2+</sup>]<sub>e</sub> nor in serum phosphorus (Pi) before and after HD with either dialysate. Group AA+Aa and group aa did not show statistically significant differences in age, female/male ratio, ratio of diabetic nephropathy, or dialysis period. Conclusions: The study results showed that the patients in group aa were more sensitive to changes in [Ca<sup>2+</sup>]<sub>e</sub> than those in group AA+Aa. Moreover, they suggested that the VDR gene polymorphism may affect parathyroid responsiveness to changes in [Ca<sup>2+</sup>]<sub>e</sub>, which in turn may influence onset and progression of hyperparathyroidism in ESRD patients.

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          Most cited references 8

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          25-Hydroxyvitamin D3 1-Hydroxylase and Vitamin D Synthesis

           K Takeyama (1997)
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            Vitamin D-receptor gene polymorphisms and bone density in prepubertal American girls of Mexican descent.

            Bone mass is under strong genetic control, and recent studies in adults have suggested that allelic differences in the gene for the vitamin D receptor may account for inherited variability in bone mass. We studied the relations of the vitamin D-receptor genotype to skeletal development and variation in the size, volume, and density of bone in children. We identified three allelic variants of the vitamin D-receptor gene using the polymerase chain reaction and three restriction enzymes (ApaI, BsmI, and TaqI) in 100 normal prepubertal American girls of Mexican descent. We then determined the relations of the different vitamin D-receptor genotypes (AA, Aa, aa, BB, Bb, bb, TT, Tt, and tt) to the cross-sectional area, cortical area, and cortical bone density of the femoral shaft and the cross-sectional area and density of the lumbar vertebrae. The vitamin D-receptor genotype was associated with femoral and vertebral bone density. Girls with aa and bb genotypes had 2 to 3 percent higher femoral bone density (P=0.008 and P=0.04, respectively) and 8 to 10 percent higher vertebral bone density (P=0.01 and P=0.03, respectively) than girls with AA and BB genotypes. There was no association between the cross-sectional area of the vertebrae or the cross-sectional or cortical area of the femur and the vitamin D-receptor genotype. The chronologic age, bone age, height, weight, body-surface area, and body-mass index did not differ significantly among girls with different vitamin D-receptor genotypes. Vitamin D-receptor gene alleles predict the density of femoral and vertebral bone in prepubertal American girls of Mexican descent.
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              The extracellular calcium-sensing receptor: its role in health and disease.

              The recent cloning of an extracellular calcium (Ca2+o)-sensing receptor (CaR) from parathyroid, kidney and other cell types has clarified the mechanisms through which Ca2+o exerts its direct actions on various cells and tissues. In the parathyroid, the CaR mediates the inhibitory effects of Ca2+o on parathyroid hormone (PTH) secretion and likely on expression of the PTH gene and parathyroid cellular proliferation. In the kidney, the receptor mediates direct inhibition of the reabsorption of divalent cations in the cortical thick ascending limb, and it likely underlies the inhibitory actions of hypercalcemia on the urinary-concentrating mechanism in the medullary thick ascending limb and inner medullary collecting duct. The identification of inherited diseases of Ca2+o-sensing that arise from mutations in the CaR gene has proven, by genetic means, the central role of the CaR in mineral ion homeostasis and the importance of the receptor in regulating the parathyroid and kidney. An allosteric CaR agonist ("calcimimetic") is currently being tested for the treatment of primary hyperparathyroidism, and CaR-based therapeutics will likely be applicable to other disorders in which CaRs are under- or overactive. Thus the discovery of the CaR and its associated diseases has documented that Ca2+o plays an essential role as an extracellular first messenger, in addition to serving its better recognized role as an intracellular second messenger.

                Author and article information

                S. Karger AG
                10 October 2001
                : 89
                : 3
                : 315-320
                aDivision of Nephrology and Hypertension, Jikei University School of Medicine, Tokyo, bNephrology and Dialysis Unit, Department of Internal Medicine, Sakura National Hospital, Sakura, and cDepartment of Clinical Physiology, and dKidney Center, Toranomon Hospital, Tokyo, Japan
                46092 Nephron 2001;89:315–320
                © 2001 S. Karger AG, Basel

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                Tables: 3, References: 28, Pages: 6
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