Risk of nephrolithiasis in primary hyperparathyroidism is associated with two polymorphisms of the calcium-sensing receptor gene

Vezzoli, Giuseppe; Scillitani, Alfredo; Corbetta, Sabrina; Terranegra, Annalisa; Dogliotti, Elena; Guarnieri, Vito; Arcidiacono, Teresa; Macrina, Lorenza; Mingione, Alessandra; Brasacchio, Caterina; Eller-Vainicher, Cristina; Cusi, Daniele; Spada, Anna; Cole, David E. C.; Hendy, Geoffrey N.; Spotti, D.; Soldati, Laura

doi:10.1007/s40620-014-0106-8

Cited by 25 publications

(31 citation statements)

References 24 publications

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“…In vitro studies showed that the minor G allele at rs67780158 caused a decrease in the transcriptional efficiency of the promoter 1 in two renal cell models 90 . Moreover recent data showed that the simultaneous presence of both rs1501899 and Arg990Gly may potentiate the kidney stone risk in patients with primary hyperparathyroidism despite their apparently opposite effects on CASR function in the kidney 91 .…”

Section: Genetic Polymorphisms Associated With Calcium Nephrolithiasismentioning

confidence: 99%

Localization and function of the renal calcium-sensing receptor

2016

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The ability to monitor changes in the ionic composition of the extracellular environment is a crucial feature that has evolved in all living organisms. The cloning and characterization of the extracellular calcium-sensing receptor (CaSR) from the mammalian parathyroid gland in the early 1990s provided the first description of a cellular, ion-sensing mechanism. This finding demonstrated how cells can detect small, physiological variations in free ionized calcium (Ca(2+)) in the extracellular fluid and subsequently evoke an appropriate biological response by altering the secretion of parathyroid hormone (PTH) that acts on PTH receptors expressed in target tissues, including the kidney, intestine, and bone. Aberrant Ca(2+) sensing by the parathyroid glands, as a result of altered CaSR expression or function, is associated with impaired divalent cation homeostasis. CaSR activators that mimic the effects of Ca(2+) (calcimimetics) have been designed to treat hyperparathyroidism, and CaSR antagonists (calcilytics) are in development for the treatment of hypercalciuric disorders. The kidney expresses a CaSR that might directly contribute to the regulation of many aspects of renal function in a PTH-independent manner. This Review discusses the roles of the renal CaSR and the potential impact of pharmacological modulation of the CaSR on renal function.

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Section: Genetic Polymorphisms Associated With Calcium Nephrolithiasismentioning

confidence: 99%

Localization and function of the renal calcium-sensing receptor

2016

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“…Moreover, Claudin 14, a protein which regulates the transport of ions ans solutes at epithelial tight junctions, is expressed at a lower level in the rs6776158 GG homozygous subjects. In these cases, nephrolithiasis may occur by another mechanism than hypercalciuria [1, 19]. …”

Section: Calcium-sensing Receptor and Other Diseasesmentioning

confidence: 99%

Diseases associated with calcium-sensing receptor

Vahé

Benomar

Espiard

et al. 2017

Orphanet J Rare Dis

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The calcium-sensing receptor (CaSR) plays a pivotal role in systemic calcium metabolism by regulating parathyroid hormone secretion and urinary calcium excretion. The diseases caused by an abnormality of the CaSR are genetically determined or are more rarely acquired. The genetic diseases consist of hyper- or hypocalcemia disorders. Hypercalcaemia disorders are related to inactivating mutations of the CASR gene either heterozygous (autosomal dominant familial benign hypercalcaemia, still named hypocalciuric hypercalcaemia syndrome type 1) or homozygous (severe neonatal hyperparathyroidism). The A986S, R990G and Q1011E variants of the CASR gene are associated with higher serum calcium levels than in the general population, hypercalciuria being also associated with the R990G variant. The differential diagnosis consists in the hypocalciuric hypercalcaemia syndrome, types 2 (involving GNA11 gene) and 3 (involving AP2S1 gene); hyperparathyroidism; abnormalities of vitamin D metabolism, involving CYP24A1 and SLC34A1 genes; and reduced GFR. Hypocalcemia disorders, which are more rare, are related to heterozygous activating mutations of the CASR gene (type 1), consisting of autosomal dominant hypocalcemia disorders, sometimes with a presentation of pseudo-Bartter’s syndrome. The differential diagnosis consists of the hypercalciuric hypocalcaemia syndrome type 2, involving GNA11 gene and other hypoparathyroidism aetiologies. The acquired diseases are related to the presence of anti-CaSR antibodies, which can cause hyper- or especially hypocalcemia disorders (for instance in APECED syndromes), determined by their functionality. Finally, the role of CaSR in digestive, respiratory, cardiovascular and neoplastic diseases is gradually coming to light, providing new therapeutic possibilities. Two types of CaSR modulators are known: CaSR agonists (or activators, still named calcimimetics) and calcilytic antagonists (or inhibitors of the CasR). CaSR agonists, such as cinacalcet, are indicated in secondary and primary hyperparathyroidism. Calcilytics have no efficacy in osteoporosis, but could be useful in the treatment of hypercalciuric hypocalcaemia syndromes.

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“…Our searching strategy identified eight papers evaluating the association between CaSR R990G gene polymorphism and the risk of urolithiasis. Of those, four papers [26][27][28][29] showed that R990G gene polymorphism was associated with the risk of urolithiasis with variable odd ratio, ranging from 1.24 to 8.07 (G vs. R). On the other hand, four other studies [30][31][32][33] failed to confirm the correlation.…”

Section: Discussionmentioning

confidence: 99%

Association between calcium-sensing receptor (CaSR) R990G, CaSR A986S, and CaSR Q1011E gene polymorphisms and the risk of urolithiasis: a meta-analysis

Daryanto

Purnomo

Gunawan

et al. 2019

Egypt J Med Hum Genet

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Backgrounds: In the last two decades, studies have been widely carried out to assess the association between singlenucleotide polymorphisms (SNPs) of calcium-sensing receptor (CaSR) gene in exon 7 and the risk of urolithiasis. However, inconsistency across the studies was reported. Therefore, our current study aimed to perform a meta-analysis concerning the association between the risk of urolithiasis and the gene polymorphisms of CaSR R990G, CaSR A986S, and CaSR Q1011E. Methods: Published papers from PubMed, Embase, Cohcrane, and Web of science were included for the study, and they were analyzed using fixed or random effect model. Results: A total of 11 papers consisting of eight papers evaluating CaSR R990G, nine papers evaluating CaSR A986S, and five papers evaluating CaSR Q1011E were included in our analysis. Our pooled calculation found that protective effect against urolithiasis was observed in R allele and RR genotype of CaSR R990G and A allele and AA genotype of CaSR A986S. Conversely, increased susceptibility to urolithiasis was found in G allele and RG genotype of CaSR R990G and S allele of CaSR A986S. Interestingly, our findings in subgroup analysis confirmed that the correlation between CaSR R990G and urolithiasis was found in Caucasian population. Meanwhile, in Asian population, the association was observed in CaSR A986S. Conclusions: CaSR R990G and CaSR A986S, but not CaSR Q1011E, are associated with the risk of urolithiasis.

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Risk of nephrolithiasis in primary hyperparathyroidism is associated with two polymorphisms of the calcium-sensing receptor gene

Abstract: We conclude that the simultaneous presence of the minor allele at rs1501899 and Arg990Gly may amplify the kidney stone risk in PHPT patients, despite their apparently opposite effects on CASR function in the kidney.

Cited by 25 publications

References 24 publications

Localization and function of the renal calcium-sensing receptor

Localization and function of the renal calcium-sensing receptor

Diseases associated with calcium-sensing receptor

Association between calcium-sensing receptor (CaSR) R990G, CaSR A986S, and CaSR Q1011E gene polymorphisms and the risk of urolithiasis: a meta-analysis

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