Polymorphisms of CASR gene increase the risk of primary hyperparathyroidism

Wang, Xiaomin; Yw, Wu; Zj, Li; Xiao, Zhao; Lv, S-M.; Xh, Wang

doi:10.1007/s40618-015-0405-5

Cited by 9 publications

(6 citation statements)

References 35 publications

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“…Studies have reported polymorphism in CaSR gene variants rs1801725, and rs1042636 are associated with various diseases, i.e., renal stone disease [10,14,20], prostate cancer [21], colorectal cancer [22], and primary HPT [23]. In our study, we have observed that individuals carrying GG genotype (rs1801725) and AA genotype (rs1042636) are associated with a high risk of developing renal stone disease.…”

Section: Discussionsupporting

confidence: 49%

Haplotype of CaSR gene is associated with risk of renal stone disease in West Indian population

et al. 2022

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Calcium is the most abundant metabolite involved in the stone matrix. The CaSR gene controls calcium homeostasis, and genetic variation in the CaSR gene could lead to the development of renal stone disease. Therefore, the current study has been designed to assess the association of genetic variants of CaSR gene polymorphisms with renal stone disease. MethodA single-centric prospective study has been carried out on a total of 300 participants (150 cases and 150 controls). Serum levels of calcium, creatinine, parathyroid hormone, and 24 Hour urine metabolites were measured. Two polymorphisms, rs1801725 and rs1042636, of the CaSR gene, have been genotyped for each participant. T-test, Chi-square, and Receiving Operative Curve (ROC) curve analysis were used for statistical analysis. ResultRenal stone patients had signi cantly higher levels of serum parathyroid hormone, creatinine, and 24hr urine metabolites in comparison to the controls. CaSR gene variants rs1801725 (GG) and rs1042636 (AA) both have shown signi cant association with renal stone disease. In addition, individuals having speci c genotypes along with metabolic abnormalities such as hypercalcemia, and hyperparathyroidism are found to be at a higher signi cant risk of developing the renal stone disease. Further, ROC analysis also showed a higher risk (54%) for individuals carrying the GG/AA haplotype. ConclusionIn the present study, the haplotype of the CaSR gene has shown an association with renal stone disease. Individuals with hyperparathyroidism and hypercalcemia and risk genotype have a higher susceptibility to developing the renal stone disease.

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Section: Discussionsupporting

confidence: 49%

Haplotype of CaSR gene is associated with risk of renal stone disease in West Indian population

et al. 2022

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“…However, a dozen cases of parathyroid adenomas associated with CASR mutations have been reported, with two families having adenoma and/or familial hyperplasia of the parathyroids with papillary microcarcinoma [7–14]. Moreover, the R990G variant of CaSR seems to be more common in the general Chinese population, but also in Chinese patients with hyperparathyroidism [15].…”

Section: Genetic Causesmentioning

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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“…(164) Role of the CaSR polymorphisms in common forms of PHPT In line with the identification of CASR mutations causing PHPT disorders with a clear Mendelian mode of inheritance, as described in previous section, common CASR single nucleotide polymorphisms (SNPs) may also influence the phenotype of PHPT, as they have been associated by genomewide association studies (GWASs) with circulating calcium and PTH concentrations in general outbred populations. (165,166) No GWASs have been performed on PHPT to date, but findings from previous association studies of limited sample size (167)(168)(169) are in line with the contention that CASR constitutes a strong candidate gene influencing the pathogenesis of more common forms of PHPT arising in the general population. Somatic CASR mutations have not been detected in parathyroid tumors from PHPT patients, (170)(171)(172)(173) and are therefore unlikely to influence their pathogenesis.…”

Section: Fhh and Phpt Caused By Germline Mutations Of The Casr And Pa...mentioning

confidence: 75%

Epidemiology, Pathophysiology, and Genetics of Primary Hyperparathyroidism

Minisola

Arnold

Belaya³

et al. 2020

Journal of Bone and Mineral Research

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In this narrative review, we present data gathered over four decades on the epidemiology, pathophysiology and genetics of primary hyperparathyroidism (PHPT). PHPT is typically a disease of postmenopausal women, but its prevalence and incidence vary globally and depend on a number of factors, the most important being the availability to measure serum calcium and parathyroid hormone levels for screening. In the Western world, the change in presentation to asymptomatic PHPT is likely to occur, over time also, in Eastern regions. The selection of the population to be screened will, of course, affect the epidemiological data (ie, general practice as opposed to tertiary center). Parathyroid hormone has a pivotal role in regulating calcium homeostasis; small changes in extracellular Ca++ concentrations are detected by parathyroid cells, which express calcium-sensing receptors (CaSRs). Clonally dysregulated overgrowth of one or more parathyroid glands together with reduced expression of CaSRs is the most important pathophysiologic basis of PHPT. The spectrum of skeletal disease reflects different degrees of dysregulated bone remodeling. Intestinal calcium hyperabsorption together with increased bone resorption lead to increased filtered load of calcium that, in addition to other metabolic factors, predispose to the appearance of calcium-containing kidney stones. A genetic basis of PHPT can be identified in about 10% of all cases. These may occur as a part of multiple endocrine neoplasia syndromes (MEN1-MEN4), or the hyperparathyroidism jaw-tumor syndrome, or it may be caused by nonsyndromic isolated endocrinopathy, such as familial isolated PHPT and neonatal severe hyperparathyroidism. DNA testing may have value in: confirming the clinical diagnosis in a proband; eg, by distinguishing PHPT from familial hypocalciuric hypercalcemia (FHH). Mutation-specific carrier testing can be performed on a proband's relatives and identify where the proband is a mutation carrier, ruling out phenocopies that may confound the diagnosis; and potentially prevention via prenatal/preimplantation diagnosis.

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Polymorphisms of CASR gene increase the risk of primary hyperparathyroidism

Abstract: Our results indicate that SNPs of CASR gene A986S (rs1081725) and R990G (rs1042636) may increase the risk of PHPT, and the polymorphisms can potentially be used as important biological markers for early diagnosis of PHPT.

Cited by 9 publications

References 35 publications

Haplotype of CaSR gene is associated with risk of renal stone disease in West Indian population

Haplotype of CaSR gene is associated with risk of renal stone disease in West Indian population

Diseases associated with calcium-sensing receptor

Epidemiology, Pathophysiology, and Genetics of Primary Hyperparathyroidism

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