R990G polymorphism of the calcium-sensing receptor and renal calcium excretion in patients with primary hyperparathyroidism

Abstract

Context: Primary hyperparathyroidism (PHPT) shows a great variability in clinical course and severity. Data concerning the association between polymorphic variants of the gene encoding the calciumsensing receptor (CaSR) and clinical characteristics of PHPT are not conclusive. Objective: To evaluate the frequency of three polymorphisms; A986S, R990G, and Q1011E of CaSR in patients with PHPT and to correlate the genotypes with clinical and biochemical parameters. Patients and methods: The study included 94 consecutive unrelated patients referred to our Departments for PHPT diagnosis and management between 2000 and 2005 and 137 age and sexmatched healthy subjects. Patients and controls were genotyped according to standard procedures. Due to the rarity of 990G allele, homozygous and heterozygous subjects were grouped in R/GCG/G set. All PHPT patients were studied for calcium metabolism parameters and renal and bone complications. Results: The proportion of CaSRvariants was similar in PHPT patients and controls. In PHPT patients, only R990G polymorphism was associated with disease parameters; in comparison with R/R, R/GCG/G patients showed lower mean serum parathyroid hormone (PTH) and phosphate levels (139.9G62.2 vs 199.9G136.3 pg/ml, P!0.05 and 0.69G0.12 vs 0.81G0.18 mmol/l, PZ0.031 respectively), higher mean 24-h urine calcium concentration and calcium excretion (9.05G2.05 vs 6.77G4.31 mmol/24 h, PZ0.012 and 67G20 vs 51G26 mmol/l GF, PZ0.039), and increased prevalence of nephrolithiasis (90.0 vs 44.2%, PZ0.007). Conclusions: The study showed that patients with PHPT, bearing the 990G allele, had lower serum PTH levels and higher urinary calcium excretion in comparison with the other genotype, suggesting an increased sensitivity of the variant receptor to extracellular calcium. Since this variant was associated with increased occurrence of nephrolithiasis, analysis of this polymorphism might help to predict renal complication of the disease.European Journal of Endocrinology 155 687-692

Clinical phenotypes of Chinese primary hyperparathyroidism patients are associated with the calcium-sensing receptor gene R990G polymorphism

“…This would render the parathyroid cells more prone to proliferation and eventually increase the risk of developing PHPT (20). However, two subsequent studies carried out in German and Italian PHPT patients did not detect any positive correlations between the A986S or R990G variants and the risk of PHPT (9,21). The different conclusions drawn from the present study and the previous studies suggest that racial differences may influence the observed associations between genotypes and PHPT.…”

“…Additional ethnic-specific studies are necessary to reach a definite conclusion. In Italian populations, the R990G allele has been found to be associated with hypercalciuria in idiopathic calcium stone formers, osteoporotic women, and patients with PHPT (9,10,27). In addition, the R990G SNP has been found to be associated with idiopathic nephrolithiasis in individuals of different ancestries including Canadian, Iranian, and European stone formers and the general population (28,29,30).…”

“…The impact of these amino acid changes on the function of CASR is not well defined. To date, inconsistent results suggesting that the A968S and R990G polymorphisms are associated with mild changes in plasma calcium, phosphate, PTH, alkaline phosphate (ALP), and urinary calcium concentrations have been reported (8,9). There are very few studies to date that have addressed CASR gene polymorphisms in Chinese patients with PHPT.…”

MECHANISMS IN ENDOCRINOLOGY: Kidney involvement in patients with primary hyperparathyroidism: an update on clinical and molecular aspects

“…Therefore, common variants of the CASR gene modulate the effect of PTH-related hypercalcaemia on renal calcium handling ( Table 4). The 990G allele, located in the cytoplasmic tail of the receptor protein, has been associated with increased renal calcium excretion in PHPT Italian patients (78,79). Two further single nucleotide polymorphisms (SNPs), located in the regulatory region of the CASR gene, rs7652589 and rs1501899, are associated with kidney stones occurrence in PHPT patients (80).…”

Antilipolytic effect of calcimimetics depends on the allelic variant of calcium-sensing receptor gene polymorphism rs1042636 (Arg990Gly)

“…This SNP has been associated with primary hypercalciuria, 8 lower circulating calcium in healthy individuals 9 and with lower plasma PTH in patients with primary or sHPT. 10,11 Patients with the glycine allele show a more pronounced suppression of PTH after administration of cinacalcet, as compared with homozygous arginine carriers. 12 Transfected cells expressing CASR with glycine in position 990 respond more strongly to a calcimimetic added to the culture medium than those with arginine.…”