[Show abstract][Hide abstract] ABSTRACT: Single nucleotide polymorphisms (SNPs) of the calcium-sensing receptor (CASR) gene at the regulatory region were associated with idiopathic calcium nephrolithiasis. To confirm their association with nephrolithiasis, we tested patients with primary hyperparathyroidism (PHPT).
A genotype-phenotype association study.
In all, 332 PHPT patients and 453 healthy controls were genotyped for the rs7652589 (G>A) and rs1501899 (G>A) SNPs sited in the noncoding regulatory region of the CASR gene. Allele, haplotype, and diplotype distribution were compared between PHPT patients and controls, and in stone forming and stone-free PHPT patients.
The allele frequency at rs7652589 and rs1501899 SNPs was similar in PHPT patients and controls. The A minor alleles at these two SNPs were more frequent in stone forming (n=157) than in stone-free (n=175) PHPT patients (rs7652589: 36.9 vs 27.1%, P=0.007; rs1501899: 37.1 vs 26.4%, P=0.003). Accordingly, homozygous or heterozygous PHPT patients for the AA haplotype (n=174, AA/AA or AA/GG diplotype) had an increased stone risk (odds ratio 1.83, 95% confidence interval 1.2-2.9, P=0.008). Furthermore, these PHPT patients had higher serum concentrations of ionized calcium and parathyroid hormone (1.50 ± 0.015 mmol/l and 183 ± 12.2 pg/ml) than patients with the GG/GG diplotype (n=145, 1.47 ± 0.011 mmol/l (P=0.04) and 150 ± 11.4 pg/ml (P=0.049)). Using a logistic regression model, the increase in stone risk in PHPT patients was predicted by AA/AA or AA/GG diplotype, the highest tertile of serum ionized calcium values and the lowest tertile of age.
Polymorphisms located in the regulatory region of the CASR gene may increase susceptibility of the PHPT patients to kidney stone production.
European Journal of Endocrinology 03/2011; 164(3):421-7. DOI:10.1530/EJE-10-0915 · 4.07 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Chronic kidney disease (CKD) is characterized by phosphate retention and reduced synthesis of 1.25(OH)2-vitamin D stimulating parathyroid hyperplasia. These changes cause a complex osteopathy, defined as renal osteodystrophy, and vascular calcification. Renal osteodystrophy increases the risk of fracture and causes deformities and disability. Vascular calcification occurs in a large proportion of hemodialysis patients and is a marker of arteriopathy. Calcifying arteriopathy induces arterial stiffness and contributes to the high cardiovascular mortality and morbidity among CKD patients. Vascular calcification results from a process of local bone formation induced by osteoblast-like cells developing in the vascular wall from resident cells. Osteoblast differentiation of resident vascular cells may be mediated by metabolic factors and may be induced by high concentrations of phosphate. Therefore, phosphate retention appears as the most detrimental factor affecting arteries in CKD patients. There is no specific therapy to revert soft tissue calcification, but calcification must be prevented in the early stages of CKD.
[Show abstract][Hide abstract] ABSTRACT: Genetic studies of calcium kidney stones evidenced the possible involvement of calcium-sensing receptor gene, vitamin D receptor gene and bicarbonate-sensitive adenylate cyclase gene, but it is uncertain which specific polymorphisms could be responsible. Thus, further studies are required to better assess the involvement of these or other genes and the interactions between different genes and between genes and environment. In addition to research in humans, the study of different strains of knock-out mice let us include the gene of phosphate reabsorption carrier NPT2, caveolin-1, protein NHERF-1, osteopontin and Tamm-Horsfall protein among the possible determinants. Further steps in the knowledge of calcium stone causes may be done using the instruments that the modern biotechnology and bioinformatics have made available to the researchers.
Clinical Cases in Mineral and Bone Metabolism 05/2008; 5(2):110-3.
[Show abstract][Hide abstract] ABSTRACT: An association between the R990G polymorphism of the CaSR gene, coding for calcium-sensing receptor, and primary hypercalciuria was found in kidney stone formers. To confirm this relationship, we investigated hypercalciuric women without stones and studied the effect of CaSR gene in human embryonic kidney cells (HEK-293). We genotyped for CaSR A986S, R990G, and Q1011E polymorphisms, 119 normocalciuric and 124 hypercalciuric women with negative history of kidney stones. Homozygous (n=2) or heterozygous (n=21) women for the 990G allele considered as one group had an increased risk to be hypercalciuric (odds ratio=5.2; P=0.001) and higher calcium excretion (P=0.005) in comparison with homozygous women for the 990R allele (n=220). HEK-293 cells were transfected with the variant allele at the three CaSR gene polymorphisms and with the most common allele with no variants. The transient increment of intracellular calcium caused by the stepwise increase of extracellular calcium was evaluated in stable transfected cells loaded with fura-2 AM. The extracellular calcium concentration producing the half-maximal intracellular calcium response was lower in HEK-293 cells transfected with the 990G allele than in those transfected with the wild-type allele (P=0.0001). Our findings indicate that R990G polymorphism results in a gain-of-function of the calcium-sensing receptor and increased susceptibility to primary hypercalciuria.
Kidney International 07/2007; 71(11):1155-62. DOI:10.1038/sj.ki.5002156 · 8.56 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Type 5 Bartter syndrome has been recently defined as a Bartter syndrome due to the most activating mutations of the calcium-sensing receptor (CaSR). It has been attributed to the inhibition exerted by CaSR activity on sodium transport in the thick ascending limb of the loop of Henle (TALH). Two monozygotic twin sisters (T1 and T2) with autosomal dominant hypocalcemia (ADH) due to a nonconservative activating CaSR mutation in the extracellular domain (K29E) were studied. They developed a Bartter-like syndrome characterized by a mild phenotype: hypokalemia occurred only at the age of 22 years; it was corrected with small doses of oral potassium in one twin, while the other twin needed no potassium supplements to maintain borderline levels of plasma potassium; alkalosis was absent; plasma renin and aldosterone production were not markedly activated. Furthermore, the natriuretic response to furosemide, a inhibitor of sodium reabsorption in the TALH, was conserved in both twins. The K29E mutation was previously reported as one of the most activating mutations of the CaSR gene leading to a very marked increase in CaSR sensitivity to calcium ions. These findings confirm that Bartter syndrome is typically associated with ADH provided that the underlying mutation of CaSR is able to produce a conspicuous gain of function. However, the phenotype of type 5 Bartter syndrome may manifest with variable severity, not directly related with the in vitro potency of the CaSR activating mutation.
Journal of nephrology 07/2006; 19(4):525-8. · 1.45 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Genetic studies of calcium kidney stones have so far assessed single candidate genes by testing linkage disequilibrium or association between a locus and stone disease. They showed the possible involvement of the calciumsensing receptor gene, vitamin D receptor gene, and bicarbonate-sensitive adenylate cyclase gene. In addition to research in humans, the study of different strains of knock-out mice let us include the gene of phosphate reabsorption carrier NPT2, caveolin-1, protein NHERF-1 modulating calcium and urate reabsorption, osteopontin and Tamm-Horsfall protein among the possible determinants. However, the interactions between genes and also between environmental factors and genes are generally considered fundamental in calcium stone formation. Thus, the genetic studies carried out to date have not led to a significant growth of the knowledge about the causes of calcium kidney stones, even though they have allowed us to assess the size of the problem and define criteria to address it. Further knowledge of the causes of calcium stones may be obtained using the instruments that modern biotechnology and bioinformatics have made available to researchers.
Giornale italiano di nefrologia: organo ufficiale della Societa italiana di nefrologia 26(1):64-72.