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

Unità Operativa di Endocrinologia e Diabetologia, Department of Medical-Surgical Sciences, University of Milan, Policlinico San Donato IRCCS, San Donato M.se, Milan, Italy, ¹ Endocrine Unit, Department of Medical Sciences and ² Laboratory of Medical Genetics, Institute of Pediatrics and Neonatology, Fondazione Ospedale Maggiore IRCCS, University of Milan, Via F Sforza 35, 20122 Milan, Italy, ³ Nephrology Unit, Postgraduate School of Nephrology, San Raffaele Scientific Institute, Milan, Italy, ⁴ Division of Endocrinology, Niguarda Hospital, Milan, Italy and ⁵ Department of Biomedical Sciences and Technology, University of Milan, Milan, Italy

(Correspondence should be addressed to A Spada; Email: anna.spada{at}unimi.it)

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 calcium-sensing 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 sex-matched 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/G+G/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/G+G/G patients showed lower mean serum parathyroid hormone (PTH) and phosphate levels (139.9 ± 62.2 vs 199.9 ± 136.3 pg/ml, P < 0.05 and 0.69 ± 0.12 vs 0.81 ± 0.18 mmol/l, P = 0.031 respectively), higher mean 24-h urine calcium concentration and calcium excretion (9.05 ± 2.05 vs 6.77 ± 4.31 mmol/24 h, P = 0.012 and 67 ± 20 vs 51 ± 26 µmol/l GF, P = 0.039), and increased prevalence of nephrolithiasis (90.0 vs 44.2%, P = 0.007).

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 sensitivityof 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.