Primary HPT shows a great variability in its clinical course and severity, which might be related to polymorphic variants of the CASR gene. The aim of the study was to evaluate the frequency of two known CASR single nucleotide polymorphisms (SNPs), i.e. G/T at codon 986 and G/A at codon 990, in a homogenous North-Italian cohort of PHPT patients compared with a sex and age matched healthy population and the possible correlation of these CASR gene variants with the clinical and biochemical characteristics of PHPT patients. SNPs were analyzed by direct sequencing in 94 PHPT unrelated patients (79 F, 15 M; age 65±13 years, plasma ionized calcium 1.52±0.15 mmol/L; serum PTH 192.7±130.9 pg/ml) and in 179 healthy subjects (148 F, 29 M). All PHPT patients were studied for renal and bone PHPT complications. The proportion of CASR variants was similar in PHPT and controls (codon 896: G/G 62% vs 66%, G/T 30% vs 28%, T/T 8% vs 6% and codon 990: A/A 88% vs 91%, A/G 10% vs 7%, G/G 2% vs 2%). The G986T polymorphisms were not associated with any clinical or biochemical PHPT parameters. Patients with 990 A/G and G/G genotype showed lower serum PTH (139.9±62.2 vs 199.9±136.3 pg/ml; P=0.02) and phosphate levels (0.69±0.12 vs 0.81±0.18 mmol/L; P=0.03). Twenty-four hour-urine calcium excretion was higher in patients with 990G (9.05±2.05 vs 6.77±4.31 mmol/24 h; P=0.012) and it was associated with higher prevalence of nephrolithiasis (90% vs 44.2%; P=0.007) than patients with A/A. In conclusion, A990G variants might increase CASR sensitivity to extracellular calcium, determining a lower PTH secretion. Moreover, at the kidney level the increased CASR sensitivity might result in the inhibition of renal calcium reabsorption and increase in calcium excretion, this phenomenon favoring nephrolithiasis.
01 - 05 Apr 2006
European Society of Endocrinology