title: 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.
authors.affiliation: Department of Nephrology, Transplantology and Internal Diseases, Poznan University of Medical Sciences, Poznań, Poland.
authors.forename: Alicja E
authors.initials: AE
authors.lastname: Grzegorzewska
authors.affiliation: Department of Internal Diseases, Pleszew Medical Center, Pleszew, Poland.
authors.forename: Mateusz
authors.initials: M
authors.lastname: Paciorkowski
authors.affiliation: Department of Biochemistry and Molecular Biology, Poznan University of Medical Sciences, Poznań, Poland.
authors.forename: Adrianna
authors.initials: A
authors.lastname: Mostowska
authors.affiliation: Department of Biochemistry and Molecular Biology, Poznan University of Medical Sciences, Poznań, Poland.
authors.forename: Bartosz
authors.initials: B
authors.lastname: Frycz
authors.affiliation: Department of Biophysics, Poznan University of Medical Sciences, Poznań, Poland.
authors.forename: Wojciech
authors.initials: W
authors.lastname: Warchoł
authors.affiliation: Institute of Bioorganic Chemistry, Polish Academy of Sciences, Poznań, Poland.
authors.forename: Ireneusz
authors.initials: I
authors.lastname: Stolarek
authors.affiliation: Institute of Bioorganic Chemistry, Polish Academy of Sciences, Poznań, Poland.
authors.forename: Marek
authors.initials: M
authors.lastname: Figlerowicz
authors.affiliation: Department of Biochemistry and Molecular Biology, Poznan University of Medical Sciences, Poznań, Poland.
authors.forename: Paweł P
authors.initials: PP
authors.lastname: Jagodziński
mesh_terms: D002318:Cardiovascular Diseases / Q000453:epidemiology / Q000235:genetics; D020022:Genetic Predisposition to Disease; D006801:Humans; D006962:Hyperparathyroidism, Secondary / Q000453:epidemiology / Q000235:genetics*; D007676:Kidney Failure, Chronic / Q000453:epidemiology* / Q000235:genetics / Q000628:therapy; D053040:Nephrolithiasis / Q000150:complications / Q000453:epidemiology* / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D044169:Receptors, Calcium-Sensing / Q000235:genetics*; D006435:Renal Dialysis
chemical_list: C095550:CASR protein, human; D044169:Receptors, Calcium-Sensing