Calcium-sensing Receptor Gene Polymorphisms Research Articles

Relationship of calcium-sensing receptor gene polymorphism CASR rs 1042636, CASR rs 1802757, and cinacalcet response among Egyptian hemodialysis patients with secondary hyperparathyroidism

Introduction: Secondary hyperparathyroidism (SHPT) is a common complication associated with morbidity and mortality among hemodialysis (HD) patients. Objectives: The current study aims to evaluate the frequency of CASR gene polymorphism variants related to parathyroid hormone (PTH) regulation (CASR rs1042636 and CASR rs1802757) and to test the hypothesis that single nucleotide polymorphisms (SNPs) in the CASR gene alter the response to cinacalcet among Egyptian HD patients with SHPT. Patients and Methods: A case-control study that included 50 HD patients with intact parathyroid hormone (iPTH) ≥300 pg/mL treated with cinacalcet for a 6-month duration and 40 healthy volunteers as a control group. Eligible patients were recruited from Ain Shams university hospitals. Blood samples were collected from patients and controls to assess allele frequencies of CASR gene polymorphism variants using real-time polymerase chain reaction (PCR), corrected calcium (Ca), phosphorus (P), Ca×P product, iPTH level, and alkaline phosphatase before and after treatment. HD patients were categorized into two groups based on the reduction percentage; responders’ patients (iPTH ≥20%) and non-responders to cinacalcet treatment. Results: Of 50 HD patients, 48 (96%) carried the rs1042636 AA wild gene, while only two (4%) carried the rs1042636 AG mutant gene, 42 (87.5%) carried the rs1802757 CC wild genotype, and 6 (12.5%) carried the CT mutant genotype. The minor alleles T and G were (6.3% and 2%) respectively, with no statistically significant difference between the patient and control groups regarding the CASR genotypes or alleles distribution. There was no significant difference between responders and non-responder’s patient groups regarding CASR genotypes or allele frequencies. Moreover, no significant correlation between CASR genotypes or alleles to delta change of Ca, P, Ca×P product, or PTH was seen. However, CASR rs1802757 CT mutant genotype was associated with a significant reduction in alkaline phosphatase levels after treatment. Conclusion: There is no significant association between the gene polymorphism CASR rs1042636 or CASR rs1802757 and the reduction in PTH levels as a response to cinacalcet treatment among Egyptian HD patients with SHPT.

Association between A986S polymorphism of CaSR gene and concentration of 25-OH vitamin D in healthy syrians

The calcium Sensing Receptor (CaSR) and vitamin D are considered as essential factors for regulation and sensing the minor changes in calcium concentrations in the extracellular matrix of cells. It is still unclear whether single nucleotide polymorphisms (SNPs) of CaSR gene have effects on vitamin D level. The aim of this study is to evaluate the relationship between CaSR gene polymorphism A986S and 25-OH vitamin D levels in healthy Syrian population. MethodsA total of 197 healthy Syrians individuals (Aged 18 to 50 years. Female: 131 and male: 66) were recruited in this study. Based on vitamin D serum concentration in serum, participants were divided into four groups: sufficiency (G1) (Vit.D > 30 ng/ml), insufficiency (G2) (Vit.D: 20–30 ng/ml), deficiency (G3) (Vit.D: 10–20 ng/ml), and severe deficiency (G4) (Vit.D < 10 ng/ml). All the subjects were genotyped at the CaSR A986S with PCR followed by SacI restriction enzyme digestion and agarose gel electrophoresis. ResultsThe frequency of genotypes A986S for the whole study participants was 59.9% (AA), and 35.5% (AS) and 4.6% (SS). Allele frequencies for A and S were 77.7% and 22.3% respectively. Frequencies of AA, AS and SS genotypes were 94.1%, 5.9% and 0% in sufficient vitamin D group, 71.1%, 26.1% and 2.2% in vitamin D insufficiency group, 60.4%, 33.3% and 6.3% in vitamin D deficiency group, and 34.8%, 58% and 7.2% in severe deficiency of vitamin D respectively. The differences between G1 group and rest groups G2, G3, G4 were statistically significant and P value were (0.038, 0.002, <0.001), respectively. In summary, there was a strong correlation between allele S and decreased vitamin D levels. Additionally, the study reported an association between normal vitamin D levels and AA genotype of the CaSR gene in healthy Syrians.

Molecular assessment of calcium-sensing receptor gene polymorphism rs1801725 in Iraqi women with osteoporosis

Molecular assessment of calcium-sensing receptor gene polymorphism rs1801725 in Iraqi women with osteoporosis

Calcium-sensing receptor gene polymorphisms and their effect on response to cinacalcet treatment in patients with secondary hyperparathyroidism in chronic kidney diseases

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Calcium-Sensing Receptor Gene Polymorphisms (CASRV1 and CASRV2) and the Physical Activity Level of Men in Lower Silesia, Poland.

Calcium-sensing receptors (CASR) are a dimeric family of C-class G-protein-coupled receptors that play a crucial role in bone and mineral metabolism by regulating parathyroid hormone (PTH) secretion, skeletal development, and urinary Ca2+ excretion. Genetic factors mainly impact bone mineral density (BMD). However, many variable factors may affect bone health, including physical activity. The aim of our study was to investigate the potential associations between calcium-sensing receptor gene polymorphisms (CASRV1 and CASRV2) and the level of physical activity in adult males from Lower Silesia, a region in the south of Poland. A total of 428 adult male inhabitants of Lower Silesia were included in the study. Their physical activity was evaluated using the International Physical Activity Questionnaire. The CASRV1 (rs 1801725, G>T, A986S) and CASRV2 (rs 761486, T>G, non-coding region) polymorphisms were determined using polymerase chain reaction (PCR) and mini-sequencing. The polymorphisms were identified with GeneScan software ver. 3.1.2. We did not observe any statistically significant differences between the total energy expenditure (total MET) and the CASRV1 and CASRV2 polymorphisms. We did not find any association between the level of physical activity and the frequency of genotypes at the polymorphic locus of the calcium-sensing receptor genes CASRV1 and CASRV2. We found that the number of hours the subjects spent in a sitting position was unrelated to the genotypes at the polymorphic locus of the calcium-sensing receptor gene CASRV1. Based on our studies, we concluded that there were no associations between CASR and physical activity in the men inhabiting Lower Silesia in Poland. Our results do not suggest any influence of the assessed genetic factors in the population variability of the level of physical activity of adults.

Calcium-sensing receptor gene polymorphism (rs7652589) is associated with calcium nephrolithiasis in the population of Yi nationality in Southwestern China.

The calcium-sensing receptor (CaSR) gene plays an important role in regulating the Ca2+ balance and reducing the risk for calcium stones. In this study, we evaluated the association of CaSR polymorphisms with calcium nephrolithiasis in the population of Yi nationality in Southwestern China. Biochemical variables were evaluated in 624 calcium nephrolithiasis patients and 470 age-matched healthy controls without a history of nephrolithiasis. CaSR polymorphisms rs7652589, rs1501899, rs1801725 (Ala986Ser), rs1042636 (Arg990Gly) and rs1801726 (Gln1011Glu) were investigated between the calcium nephrolithiasis patients and healthy controls, using direct sequencing. Compared with the healthy controls, serum creatinine and 24-hour urine calcium levels were significantly higher in calcium nephrolithiasis patients. Among these five polymorphisms, the genotypic and allelic frequency distributions of rs7652589 SNP was significantly associated with the risk of calcium nephrolithiasis. However, there were no genotypic or allelic distribution differences for rs1501899, rs1801725, rs1042636, and rs1801726 polymorphisms between calcium nephrolithiasis patients and healthy controls. Moreover, the association between rs7652589 SNP genotypes and the biochemical variables was not found. Our study showed that CaSR rs7652589 polymorphism had a significant effect on the risk of developing calcium nephrolithiasis in the population of Yi nationality in Southwestern China.

Genetic polymorphism of calcium-sensing receptor in women with breast cancer.

Breast cancer is a disease of unknown etiology, whose major risk factors are genetic alterations. Polymorphism of the calcium-sensing receptor (CaSR) has been a focus of some recent studies, due to a probable association with breast cancer risk and tumor aggressiveness. A relationship between polymorphic rs17251221 variant of the CaSR gene, and allele G (considered a gain-of-function mutation) and breast cancer risk has been stressed, despite the paucity of studies found in the literature. The present study involved 137 women (69 women with breast cancer-case; and 68 controls without breast cancer) who had 3ml of peripheral blood drawn for DNA study. Genomic DNA was extracted from leukocytes by genotyping technique with real-time polymerase chain reaction. The AG genotype (rs17251221) was present in 13 women (18.84%) from the case group and in 8 (11.76%) women from the control group (p=0.3434), while the GG genotype (rs17251221) did not occur in any group. In contrast, no statistically significant difference was observed between the AG genotype of variant rs17251221 in premenopausal case and control women (p=0.71). There was also no statistically significant difference between postmenopausal case and control patients (p=0.6851). In the current study, CaSR gene polymorphism of SNP variant rs17251221 did not show any statistically significant association with breast cancer, in both premenopausal and postmenopausal women.

Calcium-sensing receptor gene polymorphisms in patients with calcium nephrolithiasis

The calcium-sensing receptor gene (CaSR, chr. 3q13.3-21) is a candidate to explain nephrolithiasis. This review analyzes the potential role of CaSR in lithogenesis according to findings of functional and genetic studies. CaSR is a cation receptor located in the tubular cell plasma membrane. Its activation decreases calcium reabsorption in the ascending limb and distal convoluted tubule, but increases phosphate reabsorption in proximal tubules and decreases water and proton reabsorption in collecting ducts. Its effects in proximal tubules and collecting ducts can limit the calcium phosphate precipitation risk induced by the increase in calcium excretion. The nonconservative CaSR gene Arg990Gly polymorphism was associated with nephrolithiasis and hypercalciuria in different populations. Arg990Gly is located on exon 7 and produces a gain of the CaSR function. rs7652589 and rs1501899 were also associated with nephrolithiasis in patients with normal citrate excretion. These polymorphisms are located in the CaSR gene regulatory region and may modify CaSR gene promoter activity. The activating Arg990Gly polymorphism may predispose to nephrolithiasis by increasing calcium excretion. Polymorphisms at the regulatory region may predispose to nephrolithiasis by changing tubular expression of the CaSR. CaSR genotype may be a marker to identify patients prone to develop calcium nephrolithiasis.

Antilipolytic effect of calcimimetics depends on the allelic variant of calcium-sensing receptor gene polymorphism rs1042636 (Arg990Gly)

Calcium-sensing receptor polymorphism rs1042636 (Arg990Gly) affects the response to the calcimimetic cinacalcet, used to treat hypercalcemia in secondary hyperparathyroidism (sHPT) or parathyroid carcinoma. Carriers of the Arg allelle, show less parathyroid hormone secretion suppression in response to the drug. This effect was reproducible in transfected cultured human embryonic kidney cells, supporting a causal relationship on the protein level. We previously established that cinacalcet has an antilipolytic effect in isolated human adipocytes; however, there were a number of samples that did not respond to the treatment. The present work aimed to investigate whether the variable antilipolytic response to cinacalcet in adipocytes was consistent with the effect reported for the rs1042636 polymorphism. Lipolysis was assessed by measuring glycerol release after exposure to cinacalcet (10 μM) or vehicle in adipocytes isolated from 38 donors. Responsiveness was defined as lipolysis suppression (cinacalcet vs vehicle control) greater than 20%. Genotype analysis showed that 23 adipocyte donors were homozygous for Arg at position 990, 14 heterozygous and 1 homozygous Gly-Gly. Among the Arg homozygotes, one was responsive to cinacalcet, whereas five Gly carriers responded to the calcimimetic. In all, 83% of adipocytes showing response to cinacalcet carried the glycine allele, whereas in 96% of Arg-Arg individuals adipocytes did not respond to the calcimimetic (P=0.027, Fisher's exact test). Confirming sHPT observations, adipocytes from rs1042636 Gly-allele carriers show higher sensitivity to the antilipolytic action of cinacalcet. The potential benefit of cinacalcet as a suppressor of basal lipolysis and free fatty acid release in uremic patients needs to consider the rs1042636 single-nucleotide polymorphism.

Association between calcium-sensing receptor gene polymorphisms and recurrent calcium kidney stone disease: A comprehensive gene analysis

Comprehensive sequencing of the coding exons of the calcium-sensing receptor gene (CASR) was performed in a group of Iranian recurrent calcium kidney stone-formers and the results were compared with a control group. Serum and urine parameters were evaluated in 99 males aged between 30 and 55 years old with idiopathic recurrent calcium urolithiasis and in 107 men as a control group. Products of polymerase chain reaction were sequenced using forward primer until a mutation was found in that exon. Then, other cases were analysed by single-strand conformation polymorphism. Four polymorphisms were detected in CASR exons, all in the coding region of exon 7. These polymorphisms and their minor allele frequency were P748P (100%), A986S (1%), R990G (3%) and E1011Q (98%). There was a significantly higher count of 986S (p = 0.006), 990G (p = 0.006) and E1011 (p = 0.02) alleles in patients. The odds ratio (95% confidence interval) was 2.55 (1.31-4.96) in those at risk of stone disease for the 986S allele and 8.06 (1.80-35.9) for the 990G allele. Men with the RR genotype at R990G showed a significantly higher serum ionized calcium than the RG or GG group (p = 0.03). A significantly lower serum total calcium was found in subjects with the QQ than the EQ genotype with respect to the 1011 locus (p = 0.005). Furthermore, the 1011Q allele was marginally associated with hypercalciuria (p = 0.05). The 986S, 990G and 1011Q alleles were associated with a recurrent calcium kidney stone-forming state. 986S and 1011Q alleles, but not 986S, were associated with hypercalcaemia.

The clinical significance of parathyroid tissue calcium sensing receptor gene polymorphisms and expression levels in end-stage renal disease patients.

The calcium sending receptor (CaSR) allows parathyroid and kidney tubular cells to regulate PTH secretion and tubular calcium reabsorption. In the present report, we examined the relationship between CaSR gene polymorphisms and parathyroid CaSR expression and serum calcium/parathyroid hormone (PTH) levels and clinical progress in ESRD patients in the Turkish population. We genotyped the CaSR R990G and Q1011E variants in 192 end-stage renal disease (ESRD) patients by allele-specific PCR. CaSR expression in parathyroid tissues of operated 33 patients was quantified with quantitative reverse transcription-PCR. Compared with other genotypes, the ratio of both codon 990-AA and 1011-CC polymorphisms was found higher in operated patients (p = 0.001). In the total patient group PTH levels were found higher in patients with CC1011 genotype than those with CG1011 (1015.15 +/- 925.41 pg/ml; 523.84 +/- 544.6 pg/ml, respectively, p = 0.002). There were statistically important higher Ca2+ levels in the AA990 allele carrying cases than AG990 positive ones (9.3 +/- 1.0 mg/dl vs. 8.8 +/- 0.9, p = 0.006). On the other hand, the expression of CaSR in parathyroid tissue was found inversely proportional with serum PTH level (r = -0.71). Present data suggest that co-presence of CaSR gene AA990 and CC1011 alleles is a possible risk factor for bad prognosis in secondary hyperparathyroidism. Patients carrying this genotype have tendency to require operation early in their medical therapy period and need postoperative close follow up for possible recurrences.

Calcium‐sensing receptor gene polymorphisms and cardiac valvular calcification in patients with chronic renal failure: A pilot study

Cardiac valvular calcification (VC) is a frequent finding in chronic hemodialysis patients. In addition to demographic and metabolic factors, genetic susceptibility may also influence the occurrence and severity of these abnormalities and account for interindividual variability among patients. In this report, we studied the relation of calcium-sensing receptor (CaSR) gene polymorphisms to the development of VC in chronic hemodialysis patients. A total of 41 chronic hemodialysis patients (26 male, mean age 47.23 +/- 11.36 years vs. 15 females, mean age 48.13 +/- 14.66 years) undergoing treatment for more than 1 year were evaluated with transthoracic echocardiography. In patients with and without VC, CaSR gene polymorphisms (A990G, C1011G) were investigated by PCR, using allele-specific primers. In randomly chosen subjects, PCR analysis was verified by DNA sequencing. Cardiac valve calcification was detected in 21 patients (51.2%). Five of these patients (12.2%) had mitral valve calcification, 4 (9.75%) had aortic valve calcification, and 12 (29.27%) had both. In patients with VC, the frequency of the A/G genotype was slightly higher than those with no VC with a borderline P value (42.9% vs. 15%, chi(2)=3.840, P=0.050). The frequency of the C/C genotype was similar in patients with and without VC (90.5% vs. 85%, P>0.05). The results of this study are not enough to prove the role of CaSR gene polymorphisms in the development of VC. There is a need for large-scale studies on this topic.

Association between calcium sensing receptor gene polymorphisms and chronic pancreatitis in a US population: Role of serine protease inhibitor Kazal 1type and alcohol

To test the hypothesis that calcium sensing receptor (CASR) polymorphisms are associated with chronic pancreatitis (CP), and to determine whether serine protease inhibitor Kazal 1type (SPINK1) N34S or alcohol are necessary co-factors in its etiology. Initially, 115 subjects with pancreatitis and 66 controls were evaluated, of whom 57 patients and 21 controls were predetermined to carry the high-risk SPINK1 N34S polymorphism. We sequenced CASR gene exons 2, 3, 4, 5 and 7, areas containing the majority of reported polymorphisms and novel mutations. Based on the initial results, we added 223 patients and 239 controls to analyze three common nonsynonymous single nucleotide polymorphisms (SNPs) in exon 7 (A986S, R990G, and Q1011E). The CASR exon 7 R990G polymorphism was significantly associated with CP (OR, 2.01; 95% CI, 1.12-3.59; P = 0.015). The association between CASR R990G and CP was stronger in subjects who reported moderate or heavy alcohol consumption (OR, 3.12; 95% CI, 1.14-9.13; P = 0.018). There was no association between the various CASR genotypes and SPINK1 N34S in pancreatitis. None of the novel CASR polymorphisms reported from Germany and India was detected. Our United States-based study confirmed an association of CASR and CP and for the first time demonstrated that CASR R990G is a significant risk factor for CP. We also conclude that the risk of CP with CASR R990G is increased in subjects with moderate to heavy alcohol consumption.

Clinical Importance of Calcium-Sensing Receptor Gene Polymorphism Arg990Gly in the Age of Calcimimetic Therapy

Cinacalcet HCl is the first calcimimetic agent available for the therapy of secondary hyperparathyroidism (sHPT) and palliative treatment of parathyroid carcinoma. It acts on the extracellular calcium-sensing receptor (CaSR) as an allosteric activator, i.e. it leads to responses as if hypercalcaemia was present, in the face of normal or even low serum calcium levels. Its most important effect is the suppression of PTH secretion from the parathyroid chief cells. A reduction of PTH levels by 30-40% could be achieved in about 70% of patients with sHPT and maintained for at least two years in clinical studies. Doses required to meet the treatment goal range from 30mg to 180mg per day. There is evidence that one reason for the variability in the response to cinacalcet is a polymorphism (Arg990Gly) in the intracellular tail of the CaSR molecule. It is one of three SNPs in exon 7 of the CaSR gene, the other two being Ala986Ser and Glu1011Gln. Arg990Gly CaSR molecules (with glycine in position 990) appear to be more sensitive to cinacalcet HCl than those with arginine in this position. They are also more sensitive to calcium ions and therefore, more effective than the arginine variant in suppressing PTH secretion at hypercalcaemic levels. In primary hyperparathyroidism, the presence of Arg990Gly leads to less severe clinical courses. Keywords: parathyroid hormone, cinacalcet, bio-intact PTH (biPTH), primary hyperparathyroidism, CaSR gene polymorphisms

Calcium-sensing receptor gene polymorphism Arg990Gly and its possible effect on response to cinacalcet HCl

Cinacalcet, a novel calcimimetic compound, is effective in reducing parathyroid hormone (PTH) levels in approximately 70% of patients with secondary hyperparathyroidism. However, interindividual variations in the dose required to achieve the treatment goal have been noted in clinical studies. Our investigation examined the genetic polymorphisms of the calcium-sensing receptor (CaSR) gene as one possible cause of the different responses to cinacalcet. We report data on seven end-stage renal failure patients who were treated with regular haemodialysis and who participated in clinical trials of cinacalcet. All patients had secondary hyperparathyroidism with baseline intact PTH (iPTH) levels greater than 600 pg/ml. Three patients were male and four female with a mean+/-SD age of 60+/-12 years. DNA was extracted from peripheral lymphocytes. An area in exon 7 of the CaSR gene was amplified by the polymerase chain reaction and sequenced. Mean+/-SD baseline iPTH was 1086+/-189 pg/ml. The five patients without Arg990Gly demonstrated a 29.7+/-4.0% (+/-SEM) reduction in iPTH from individual baseline. One patient was found to be homozygous for the Arg990Gly polymorphism and another was heterozygous for both arginine and glycine alleles. The homozygous patient showed a significantly higher sensitivity to cinacalcet compared to the other patients (P=0.003) with a 76.3+/-7.7% reduction in iPTH from baseline. No polymorphisms were noted in codons 986 or 1011. This preliminary study points to the possibility that patients homozygous for glycine at the 990 position in exon 7 of the CaSR may be more sensitive to the calcimimetic drug cinacalcet compared to those who are homozygous for arginine at that location.

Calcium-sensing receptor gene polymorphism is not associated with bone mineral density in Italian postmenopausal women.

Calcium-sensing receptor (CaR) is a candidate gene for osteoporosis susceptibility. Several CaR polymorphisms have been identified and an association between the A986S genotype and serum calcium levels has been found in Canadian postmenopausal women. We investigated whether the presence of 986S allele was associated with bone mineral density (BMD) and osteoporotic fractures. The study group consisted of 164 Italian postmenopausal women without fragility fracture (Fx(-)) and 55 women with fracture (Fx(+)). A fragment of exon 7 of CaR gene containing three polymorphisms (A986S, R990G and Q1011E) was amplified by PCR and sequenced. Anthropometric characteristics and BMD were evaluated. The A986S polymorphism was the most commonly observed (27.9%), whereas the other two CaR polymorphisms, R990G and Q1011E, occurred in a minority of cases (8.8 and 5.5% respectively). There was no significant difference in the frequency distribution of any CaR allele between Fx(-) and Fx(+) patients. Body mass index was found to predict BMD at the lumbar spine and femoral neck. The A986S polymorphism and Years since menopause were not independent predictors of BMD at any site. As far as fracture occurrence, there was no statistically significant difference in the prevalence of fractures between women carrying or not carrying the 986S allele. Our data do not support a role of A986S CaR polymorphism in BMD and in the prevalence of fragility fractures in Italian postmenopausal women.

Calcium-sensing receptor gene polymorphisms in primary hyperparathyroidism

The calcium-sensing receptor (CaR) polymorphism A986S has been found to be associated with higher serum calcium levels in normal subjects, suggesting that this amino acid change might decrease the inhibitory activity of the mutated receptor, render the parathyroid cells more prone to proliferate, and eventually increase the risk of developing primary hyperparathyroidism (PHPT). The aim of the present study was to investigate the frequency of this and other 2 known CaR polymorphisms (R990G and Q1011 E) in patients with PHPT and their effect on its phenotype. We studied 103 Italian patients with PHPT and 148 healthy Italian subjects and we compared the results in 50 pairs matched for sex, age and geographic provenience. A fragment of exon 7 of the CaR gene, containing the 3 polymorphic loci of interest (A986S, R990G, and Q1011E), was amplified by PCR and sequenced. Serum calcium and PTH levels, BMD and other biochemical and clinical parameters were evaluated. The frequency distribution of the A9865, R990G, and Q1011 E polymorphisms in the 103 PHPT patients was 39.8%, 5.8%, and 2.0%, respectively. There was no difference in the frequency of the 3 CaR polymorphisms in the 50 matched pairs of patients and controls. We found no significant difference in several clinical and biochemical parameters between PHPT patients carrying or not the 986S allele. Finally, no relationship was observed between the 986S genotype and total and ionized serum calcium in control subjects. The A986S CaR polymorphism is the most common in Italian PHPT patients and the allotype AS does not appear to play a relevant role in the pathogenesis of PHPT and its severity. The A986S polymorphism does not correlate with serum calcium levels in normal Italian subjects.

Calcium-sensing receptor gene polymorphism affects the parathyroid response to moderate hypercalcemic suppression in patients with end-stage renal disease.

The basic mechanism of secondary hyperparathyroidism is still unclear, but a change in Ca2+ sensing by parathyroid cells is possibly involved in this uremic complication. A rightward shift of the calcium set-point and an increase of the minimum secretion rate have been found in secondary hyperparathyroidism, indicating abnormal calcium sensing. We evaluated the effect of calcium sensing receptor (CaR) gene polymorphism (codon G990R) on the response of the parathyroid gland to moderate hypercalcemic suppression in 77 ESRD patients on regular hemodialysis (HD using 2.5 mEq/l Ca2+ dialysate). All patients underwent an HD session with 3.0 mEq/l Ca2+ dialysate to suppress parathyroid hormone (PTH). Then we investigated the effect of CaR gene polymorphism on the parathyroid response to hypercalcemic stimulation. Patients were divided into 3 groups on the basis of genotype (GG = 33 patients (42.9%), GR = 39 patients (50.6%), RR = 5 patients (6.5%)). Baseline intact PTH levels in patients without the R allele were not significantly different from those in patients with the R allele (GG group, 181.4 +/- 31.1 pg/ml vs. GR and RR groups, 230 +/- 51.2 pg/ml: mean +/- SEM). The significant effect of moderate hypercalcemic suppression on the intact PTH level was observed in the GG group (p < 0.01) but not in the GR and RR groups, despite the identical increase in Ca2+. Our results suggest that CaR gene polymorphism (codon G990R) influences the responsiveness of the parathyroid gland to changes of extracellular Ca2+ in ESRD patients. The glands of patients with the GG genotype of the CaR gene may be more sensitive to extracellular Ca2+ changes.