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

Calcium-sensing receptor polymorphism rs1042636 (Arg990Gly) affects the response to the calcimimetic cinacalcet, used to treat hypercalcemia in secondary hyperparathyroidism (sHPT) or parathyroid carcinoma. Carriers of the Arg allelle, show less parathyroid hormone secretion suppression in response to the drug. This effect was reproducible in transfected cultured human embryonic kidney cells, supporting a causal relationship on the protein level. We previously established that cinacalcet has an antilipolytic effect in isolated human adipocytes; however, there were a number of samples that did not respond to the treatment. The present work aimed to investigate whether the variable antilipolytic response to cinacalcet in adipocytes was consistent with the effect reported for the rs1042636 polymorphism. Lipolysis was assessed by measuring glycerol release after exposure to cinacalcet (10 µM) or vehicle in adipocytes isolated from 38 donors. Responsiveness was defined as lipolysis suppression (cinacalcet vs vehicle control) greater than 20%. Genotype analysis showed that 23 adipocyte donors were homozygous for Arg at position 990, 14 heterozygous and 1 homozygous Gly-Gly. Among the Arg homozygotes, one was responsive to cinacalcet, whereas five Gly carriers responded to the calcimimetic. In all, 83% of adipocytes showing response to cinacalcet carried the glycine allele, whereas in 96% of Arg-Arg individuals adipocytes did not respond to the calcimimetic (P=0.027, Fisher's exact test). Confirming sHPT observations, adipocytes from rs1042636 Gly-allele carriers show higher sensitivity to the antilipolytic action of cinacalcet. The potential benefit of cinacalcet as a suppressor of basal lipolysis and free fatty acid release in uremic patients needs to consider the rs1042636 single-nucleotide polymorphism.

Calcium-sensing receptor gene polymorphism Arg990Gly and its possible effect on response to cinacalcet HCl.

Cinacalcet, a novel calcimimetic compound, is effective in reducing parathyroid hormone (PTH) levels in approximately 70% of patients with secondary hyperparathyroidism. However, interindividual variations in the dose required to achieve the treatment goal have been noted in clinical studies. Our investigation examined the genetic polymorphisms of the calcium-sensing receptor (CaSR) gene as one possible cause of the different responses to cinacalcet. We report data on seven end-stage renal failure patients who were treated with regular haemodialysis and who participated in clinical trials of cinacalcet. All patients had secondary hyperparathyroidism with baseline intact PTH (iPTH) levels greater than 600 pg/ml. Three patients were male and four female with a mean+/-SD age of 60+/-12 years. DNA was extracted from peripheral lymphocytes. An area in exon 7 of the CaSR gene was amplified by the polymerase chain reaction and sequenced. Mean+/-SD baseline iPTH was 1086+/-189 pg/ml. The five patients without Arg990Gly demonstrated a 29.7+/-4.0% (+/-SEM) reduction in iPTH from individual baseline. One patient was found to be homozygous for the Arg990Gly polymorphism and another was heterozygous for both arginine and glycine alleles. The homozygous patient showed a significantly higher sensitivity to cinacalcet compared to the other patients (P=0.003) with a 76.3+/-7.7% reduction in iPTH from baseline. No polymorphisms were noted in codons 986 or 1011. This preliminary study points to the possibility that patients homozygous for glycine at the 990 position in exon 7 of the CaSR may be more sensitive to the calcimimetic drug cinacalcet compared to those who are homozygous for arginine at that location.