Association of Polymorphic Alleles of the Calcium-Sensing Receptor Gene with Parathyroid Hormone Secretion in Hemodialysis Patients

Abstract

The present study was performed to investigate the association of calcium-sensing receptor (CaSR) genotypes with parathyroid hormone (PTH) secretion in hemodialysis patients. Subjects were 122 Japanese hemodialysis patients, including 39 patients with diabetes mellitus (DM). The CaSR polymorphisms tested were codon 990 in intracellular domain (A/A, A/G, and G/G groups) as well as T to C base change of intron 4 (T/T, T/C, and C/C groups). Statistical analysis of these polymorphisms revealed that the serum PTH level was significantly higher in the A/A group than in the G/G group in the former. In addition, the serum PTH level was also significantly higher in patients displaying C allele, as compared with the T/T group in the latter. This association of two polymorphisms with the serum PTH level was observed only in non-DM patients. Although two polymorphisms affected the PTH level independently, patients who possessed both genotypes (AAC+) had a markedly high level of PTH not only in the non-DM group but also in the DM group. The present findings indicate the possibility of the prediction for the extensive progression of secondary hyperparathyroidism through analyzing the CaSR polymorphisms in chronic hemodialysis patients.

Influence of Calcium-Sensing Receptor Gene on Urinary Calcium Excretion in Stone-Forming Patients

“…We propose that the 990Gly allele increases CaSR sensitivity or response to Ca ions. Accordingly, PTH secretion could be more inhibited by the 990Gly allele, in agreement with previous findings in uremic patients (23).…”

“…The functional importance of exon 7 polymorphisms has been suggested by the lower plasma Ca concentration in healthy subjects carrying the allele 986Ser (12) and by the lower plasma PTH level in Japanese uremic patients carrying the allele 990Gly (23). Genetic polymorphisms of CASR exon 7 could account for the phenotype variability of a quantitative multifactorial trait such as Ca excretion.…”

Calcimimetic R-568 effects on activity of R990G polymorphism of calcium-sensing receptor

“…Moreover, we demonstrated that transfection of the 990G variant in HEK-293 cells induced a gain-of-function of the receptor (Vezzoli et al 2007). In agreement with the in vitro phenotype, patients with primary or secondary hyperparathyroidism (PHPT and SHPT) with the 990G allele were found to have lower levels of serum PTH (Yamauchi et al 2001, Scillitani et al 2004, Corbetta et al 2007a, Wang et al 2007) and ionized calcium (Yano et al 2000). Accordingly, the 990R allele was found to be associated with higher levels of both PTH and ionized calcium in comparison with 990G carriers in healthy Chinese women (Yokoyama et al 2002).…”

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.…”