Primary hyperparathyroidism and the presence of kidney stones are associated with different haplotypes of the calcium-sensing receptor

Alfredo Scillitani, Vito Guarnieri, Claudia Battista, Simona De Geronimo, Lucia Anna Muscarella, Iacopo Chiodini, Mauro Cignarelli, Salvatore Minisola, Francesco Bertoldo, Cristiano M. Francucci, Nazzarena Malavolta, Alessandro Piovesan, Maria Lucia Mascia, Silvana Muscarella, Geoffrey N. Hendy, Leonardo D'Agruma, David E C Cole

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Abstract

Introduction: Three single-nucleotide polymorphisms in the calcium-sensing receptor gene (CASR) encoding the missense substitutions A986S, R990G, and Q1011E have been associated with normal variation in extracellular calcium homeostasis, both individually and in haplotype combination. The aim of this study was to examine haplotype associations in primary hyperparathyroidism (PHPT). Patients and Methods: Patients with sporadic PHPT (n = 237) were recruited from endocrine clinics and healthy controls (n = 433) from a blood donor clinic, and levels of serum calcium, albumin, and PTH were measured. In PHPT patients, urinary calcium/creatinine clearances and bone mineral density at spine and femoral neck were measured and the presence of kidney stones and vertebral fractures identified. The CASR single-nucleotide polymorphisms were haplotyped by allele-specific sequencing. Results: Four haplotypes (ARQ, SRQ, AGQ, and ARE) of eight were observed, in keeping with significant linkage disequilibrium, but haplotype frequencies did not show significant Hardy-Weinberg disequilibrium. The SRQ haplotype was more common in PHPT (125 of 474 alleles) than in controls (170 of 866 alleles, P = 0.006) and showed a significant (P = 0.006) gene-dosage effect. There was no significant association between haplotype and bone mineral density or fractures, but association with kidney stones was significant (P = 0.0007). In the stone-forming subgroup, the SRQ haplotype was underrepresented and AGQ overrepresented. Patients bearing the AGQ haplotype had an odds ratio of 3.8 (95% confidence interval, 1.30-11.3) for presentation with renal stones compared with the rest. Conclusion: Our data indicate that the CASR SRQ haplotype is significantly associated with PHPT in our population. Within the PHPT patient population, the AGQ haplotype is significantly associated with kidney stones.

Original languageEnglish
Pages (from-to)277-283
Number of pages7
JournalJournal of Clinical Endocrinology and Metabolism
Volume92
Issue number1
DOIs
Publication statusPublished - Jan 2007

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Calcium-Sensing Receptors
Kidney Calculi
Primary Hyperparathyroidism
Haplotypes
Genes
Calcium
Polymorphism
Minerals
Bone
Bearings (structural)
Nucleotides
Association reactions
Gene encoding
Albumins
Creatinine
Blood
Substitution reactions
Alleles
Bone Density
Single Nucleotide Polymorphism

ASJC Scopus subject areas

  • Biochemistry
  • Endocrinology, Diabetes and Metabolism

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Primary hyperparathyroidism and the presence of kidney stones are associated with different haplotypes of the calcium-sensing receptor. / Scillitani, Alfredo; Guarnieri, Vito; Battista, Claudia; De Geronimo, Simona; Muscarella, Lucia Anna; Chiodini, Iacopo; Cignarelli, Mauro; Minisola, Salvatore; Bertoldo, Francesco; Francucci, Cristiano M.; Malavolta, Nazzarena; Piovesan, Alessandro; Mascia, Maria Lucia; Muscarella, Silvana; Hendy, Geoffrey N.; D'Agruma, Leonardo; Cole, David E C.

In: Journal of Clinical Endocrinology and Metabolism, Vol. 92, No. 1, 01.2007, p. 277-283.

Research output: Contribution to journalArticle

Scillitani, Alfredo ; Guarnieri, Vito ; Battista, Claudia ; De Geronimo, Simona ; Muscarella, Lucia Anna ; Chiodini, Iacopo ; Cignarelli, Mauro ; Minisola, Salvatore ; Bertoldo, Francesco ; Francucci, Cristiano M. ; Malavolta, Nazzarena ; Piovesan, Alessandro ; Mascia, Maria Lucia ; Muscarella, Silvana ; Hendy, Geoffrey N. ; D'Agruma, Leonardo ; Cole, David E C. / Primary hyperparathyroidism and the presence of kidney stones are associated with different haplotypes of the calcium-sensing receptor. In: Journal of Clinical Endocrinology and Metabolism. 2007 ; Vol. 92, No. 1. pp. 277-283.
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abstract = "Introduction: Three single-nucleotide polymorphisms in the calcium-sensing receptor gene (CASR) encoding the missense substitutions A986S, R990G, and Q1011E have been associated with normal variation in extracellular calcium homeostasis, both individually and in haplotype combination. The aim of this study was to examine haplotype associations in primary hyperparathyroidism (PHPT). Patients and Methods: Patients with sporadic PHPT (n = 237) were recruited from endocrine clinics and healthy controls (n = 433) from a blood donor clinic, and levels of serum calcium, albumin, and PTH were measured. In PHPT patients, urinary calcium/creatinine clearances and bone mineral density at spine and femoral neck were measured and the presence of kidney stones and vertebral fractures identified. The CASR single-nucleotide polymorphisms were haplotyped by allele-specific sequencing. Results: Four haplotypes (ARQ, SRQ, AGQ, and ARE) of eight were observed, in keeping with significant linkage disequilibrium, but haplotype frequencies did not show significant Hardy-Weinberg disequilibrium. The SRQ haplotype was more common in PHPT (125 of 474 alleles) than in controls (170 of 866 alleles, P = 0.006) and showed a significant (P = 0.006) gene-dosage effect. There was no significant association between haplotype and bone mineral density or fractures, but association with kidney stones was significant (P = 0.0007). In the stone-forming subgroup, the SRQ haplotype was underrepresented and AGQ overrepresented. Patients bearing the AGQ haplotype had an odds ratio of 3.8 (95{\%} confidence interval, 1.30-11.3) for presentation with renal stones compared with the rest. Conclusion: Our data indicate that the CASR SRQ haplotype is significantly associated with PHPT in our population. Within the PHPT patient population, the AGQ haplotype is significantly associated with kidney stones.",
author = "Alfredo Scillitani and Vito Guarnieri and Claudia Battista and {De Geronimo}, Simona and Muscarella, {Lucia Anna} and Iacopo Chiodini and Mauro Cignarelli and Salvatore Minisola and Francesco Bertoldo and Francucci, {Cristiano M.} and Nazzarena Malavolta and Alessandro Piovesan and Mascia, {Maria Lucia} and Silvana Muscarella and Hendy, {Geoffrey N.} and Leonardo D'Agruma and Cole, {David E C}",
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T1 - Primary hyperparathyroidism and the presence of kidney stones are associated with different haplotypes of the calcium-sensing receptor

AU - Scillitani, Alfredo

AU - Guarnieri, Vito

AU - Battista, Claudia

AU - De Geronimo, Simona

AU - Muscarella, Lucia Anna

AU - Chiodini, Iacopo

AU - Cignarelli, Mauro

AU - Minisola, Salvatore

AU - Bertoldo, Francesco

AU - Francucci, Cristiano M.

AU - Malavolta, Nazzarena

AU - Piovesan, Alessandro

AU - Mascia, Maria Lucia

AU - Muscarella, Silvana

AU - Hendy, Geoffrey N.

AU - D'Agruma, Leonardo

AU - Cole, David E C

PY - 2007/1

Y1 - 2007/1

N2 - Introduction: Three single-nucleotide polymorphisms in the calcium-sensing receptor gene (CASR) encoding the missense substitutions A986S, R990G, and Q1011E have been associated with normal variation in extracellular calcium homeostasis, both individually and in haplotype combination. The aim of this study was to examine haplotype associations in primary hyperparathyroidism (PHPT). Patients and Methods: Patients with sporadic PHPT (n = 237) were recruited from endocrine clinics and healthy controls (n = 433) from a blood donor clinic, and levels of serum calcium, albumin, and PTH were measured. In PHPT patients, urinary calcium/creatinine clearances and bone mineral density at spine and femoral neck were measured and the presence of kidney stones and vertebral fractures identified. The CASR single-nucleotide polymorphisms were haplotyped by allele-specific sequencing. Results: Four haplotypes (ARQ, SRQ, AGQ, and ARE) of eight were observed, in keeping with significant linkage disequilibrium, but haplotype frequencies did not show significant Hardy-Weinberg disequilibrium. The SRQ haplotype was more common in PHPT (125 of 474 alleles) than in controls (170 of 866 alleles, P = 0.006) and showed a significant (P = 0.006) gene-dosage effect. There was no significant association between haplotype and bone mineral density or fractures, but association with kidney stones was significant (P = 0.0007). In the stone-forming subgroup, the SRQ haplotype was underrepresented and AGQ overrepresented. Patients bearing the AGQ haplotype had an odds ratio of 3.8 (95% confidence interval, 1.30-11.3) for presentation with renal stones compared with the rest. Conclusion: Our data indicate that the CASR SRQ haplotype is significantly associated with PHPT in our population. Within the PHPT patient population, the AGQ haplotype is significantly associated with kidney stones.

AB - Introduction: Three single-nucleotide polymorphisms in the calcium-sensing receptor gene (CASR) encoding the missense substitutions A986S, R990G, and Q1011E have been associated with normal variation in extracellular calcium homeostasis, both individually and in haplotype combination. The aim of this study was to examine haplotype associations in primary hyperparathyroidism (PHPT). Patients and Methods: Patients with sporadic PHPT (n = 237) were recruited from endocrine clinics and healthy controls (n = 433) from a blood donor clinic, and levels of serum calcium, albumin, and PTH were measured. In PHPT patients, urinary calcium/creatinine clearances and bone mineral density at spine and femoral neck were measured and the presence of kidney stones and vertebral fractures identified. The CASR single-nucleotide polymorphisms were haplotyped by allele-specific sequencing. Results: Four haplotypes (ARQ, SRQ, AGQ, and ARE) of eight were observed, in keeping with significant linkage disequilibrium, but haplotype frequencies did not show significant Hardy-Weinberg disequilibrium. The SRQ haplotype was more common in PHPT (125 of 474 alleles) than in controls (170 of 866 alleles, P = 0.006) and showed a significant (P = 0.006) gene-dosage effect. There was no significant association between haplotype and bone mineral density or fractures, but association with kidney stones was significant (P = 0.0007). In the stone-forming subgroup, the SRQ haplotype was underrepresented and AGQ overrepresented. Patients bearing the AGQ haplotype had an odds ratio of 3.8 (95% confidence interval, 1.30-11.3) for presentation with renal stones compared with the rest. Conclusion: Our data indicate that the CASR SRQ haplotype is significantly associated with PHPT in our population. Within the PHPT patient population, the AGQ haplotype is significantly associated with kidney stones.

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