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.
Highlights
Calcium (Ca) stones contribute to nephrolithiasis-related end-stage renal disease (ESRD), which requires renal replacement therapy (RRT) in 26.7% of cases
We have shown that an epistatic interaction between the CaSR gene (CASR) rs7652589 single nucleotide polymorphism (SNP) and CCL2 rs1024611 is associated with nephrolithiasis-related end stage renal disease (ESRD) requiring regular dialysis treatment
The AA genotype of CASR rs7652589 SNP appears to be independently related to higher concentrations of serum total Ca and higher frequency of serum parathyroid hormone (PTH) concentrations exceeding 500 pg/ml, but not to serum P concentration and serum total alkaline phosphatase (ALP) activity
Summary
Calcium (Ca) stones contribute to nephrolithiasis-related end-stage renal disease (ESRD), which requires renal replacement therapy (RRT) in 26.7% of cases. Calcimimetics, allosteric activators of CaSR, provide an effective means of reducing parathyroid hormone (PTH) secretion in such patients[8]. CaSR in parathyroid cells is sensitive to ionized Ca concentration and regulates PTH secretion[14]. In 2000, Yano et al.[9] demonstrated the association of CASR alleles (codon 990) with PTH secretion in HD patients. In 2002, the CASR R990G polymorphism was shown to influence the response of the parathyroid glands to changes in extracellular ionized Ca in HD patients. The CASR R990G polymorphism, which was investigated in small groups (n ≤ 20) of patients with primary HPT related to type 1 multiple endocrine neoplasia and in patients with sHPT, was not associated with the efficacy profile of cinacalcet[19]
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