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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.

SUBMITTER: Grzegorzewska AE

PROVIDER: S-EPMC5064403 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

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

Grzegorzewska Alicja E AE Paciorkowski Mateusz M Mostowska Adrianna A Frycz Bartosz B Warchoł Wojciech W Stolarek Ireneusz I Figlerowicz Marek M Jagodziński Paweł P PP

Scientific reports 20161014

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 th ...[more]

PMID: 27739473

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Project description:Abstract The dysregulation of systemic calcium homeostasis during malignancy is common in most patients with high-grade tumors. The associated comorbidity is known as cancer-induced hypercalcemia (CIH) which affects up to 30% of cases, in the absence of metastasis. In the course of breast cancer progression, the secretion of parathyroid hormone-related protein (PTHrP) by tumor cells and the associated destruction of bone tissues, leads to a progressive increase in systemic calcium or CIH. The increase in circulating Ca2+ is sensed by the calcium-sensing receptor (CaSR), which plays a significant role in maintaining Ca2+ homeostasis. More than 200 mutations and single nucleotide polymorphisms (SNPs) in the CaSR gene have been described, including the A986S CaSR at rs1801725 and Q1011E CaSR at rs1801726 SNPs with reduced sensitivity to Ca2+. Interestingly, high circulating Ca2+ is associated with aggressive breast tumors in premenopausal women and larger tumors in postmenopausal women; however, the contribution of the CaSR in breast cancer progression remains poorly understood. Unlike SNPs at rs1801726, up to 20% of breast cancer patients with SNPs at rs1801725 may be predisposed to higher circulating Ca2+ in the course of their disease. Since breast cancer frequently metastasizes to Ca2+ rich skeletal tissues, we hypothesize that the development of CIH and subsequent desensitization of the CaSR by sustained high Ca2+ is critical for both the adaptation of TNBC cells to CIH in Ca2+ rich microenvironments and TNBC progression. Our preliminary data reveal that the expression level and mutational status of the CaSR is cell type-specific, and that sustained high Ca2+ desensitizes the receptor, but promotes tumor cell growth and motility. Sustained high Ca2+ also triggers the expression of metastasis promoting genes, including the cancer/testis antigen, MAGEC2, and Plasminogen Activator Inhibitor, PAI-2, potentially via the early response genes FOS/FOSB. In addition, our preliminary data show that the A986S SNP is associated with hypercalcemia, secondary malignancy of bone and respiratory organs, and deficiency of humoral immunity. This study provides novel insights into not only the adaptation of TNBC cells to high circulating Ca2+, but also suggests that mutations of the CaSR at rs1801725 are predictive of the likelihood for metastasis to lungs and bone.

Dataset Information

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

Publications

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

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