Associations of the calcium-sensing receptor gene CASR rs7652589 SNP with nephrolithiasis and secondary hyperparathyroidism in haemodialysis patients

Abstract

Nephrolithiasis, secondary hyperparathyroidism (sHPT), and cardiovascular complications are associated with disturbances in Ca handling and contribute to morbidity/mortality during haemodialysis (HD). Calcimimetics, activators of the calcium-sensing receptor (CaSR), provide an effective means of reducing parathyroid hormone (PTH) secretion in sHPT. Polymorphism in CaSR gene (CASR) influences Ca-related parameters, however it was not shown in HD patients for CASR rs7652589. The minor allele at this polymorphism modifies the binding sites of transcription factors and CaSR expression. We hypothesized that CASR rs7652589 variants may also influence CaSR in end stage renal disease (ESRD). We aimed to determine the associations of rs7652589 with nephrolithiasis-related ESRD, Ca, P, ALP, PTH, response to treatment with cinacalcet, prevalence of coronary artery disease, and all-cause/cardiovascular mortality in HD patients (n = 1162). Healthy individuals (n = 918) were controls. This study shows that the A allele of rs7652589 is a risk allele for nephrolithiasis-related ESRD. The AA genotype is associated with more severe sHPT (higher Ca and PTH concentrations). The A allele is associated with reduced CaSR transcript level in peripheral blood mononuclear cells. According to computational analysis, potential binding sites for GLI3, AHR and TP53 are removed by the A allele, whereas binding sites for SOX18 and TP63 are created.

The Calcium-Sensing Receptor Gene Polymorphism rs1801725 and Calcium-Related Phenotypes in Hemodialysis Patients

“…Treatment with cinacalcet (Mimpara, Amgen Europe, Breda, Netherlands) at a daily dose of 30 mg was started in 245 patients with PTH exceeding 500 pg/mL. Among this group, there were 161 subjects analyzed in the previous study concerning CASR rs7652589 SNP [6]. Patients who showed serum PTH of 1000 pg/mL or higher before the planned treatment with cinacalcet underwent 99mTc-MIBI scintigraphy.…”

“…Among the studied group (n = 1215), there was 1017 (83.7%) individuals genotyped for CASR rs7652589 SNP and vitamin D signaling pathway gene SNPs in our previous study [6]. …”

“…Other CASR SNPs, rs7652589 [6] and rs1801725 [7], were individually involved in serum PTH levels in HD patients. It is not clear whether haplotypes of these SNPs are also associated with PTH levels, and whether they interact with vitamin D pathway genes or not.…”

“…In HD patients, rs7652589 SNP correlated with nephrolithiasis-related ESRD without interaction with SNPs of vitamin D signaling pathway genes [6]. …”

“…Studies of the association between CASR and the response to treatment with the calcimimetic agent cinacalcet included several CASR SNPs [6-9] and showed that CASR R990G (rs1042636) influences the response to calcimimetics in patients with sHPT [9]. …”