Blood ionized calcium is associated with clustered polymorphisms in the carboxyl-terminal tail of the calcium-sensing receptor

Alfredo Scillitani, Vito Guarnieri, Simona De Geronimo, Lucia Anna Muscarella, Claudia Battista, Leonardo D'Agruma, Francesco Bertoldo, Cinzia Florio, Salvatore Minisola, Geoffrey N. Hendy, David E C Cole

Research output: Contribution to journalArticle

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Abstract

Blood ionized calcium (iCa) is a quantitative trait subject to genetic influence. iCa is maintained in a narrow range through the action of the calcium-sensing receptor (CASR) controlling PTH secretion and calcium excretion. A CASR single nucleotide polymorphism (SNP) prevalent in Caucasian populations (A986S) has shown significant association with iCa in a cohort of young women, but association with the neighboring SNPs, R990G and Q1011E, has not been examined. We studied 377 unrelated admits (184 men and 193 women) recruited as healthy adults from a blood donor clinic. The subjects were not taking any medications, nor did they have disorders of calcium metabolism. Relative frequencies for the CASR 986S, 990G, and 1011E minor alleles were 24%, 4%, and 3% respectively. At the A986S locus, subjects with the AA genotype had significantly lower iCa (P = 0.0001) than subjects with one or two S alleles (mean ± SE, 1.221 ± 0.003 vs. 1.239 ± 0.003 mmol/liter). For the R990G site, subjects with the RR genotype had higher iCa than those with one copy of the 990G allele (1.230 ± 0.002 vs. 1.213 ± 0.007 mmol/liter; P = 0.032). With respect to the 1011 locus, iCa was lower in QQ genotype subjects than in the QE group (1.227 ± 0.002 vs. 1.255 ± 0.008 mmol/liter; P = 0.002). After resolution of phase for the doubly heterozygous subjects, analysis was conducted on haplotypes across all three loci. As expected, subjects with SRQ and ARE haplotypes are relatively hypercalcemic, and those with AGQ are hypocalcemic, relative to subjects with the common ARQ haplotype. Multiple regression analysis with clinical covariates (age, ses and menopausal status, creatinine, and PTH) showed that 16.5% of the total variance in iCa may be explained, and the seven CASR haplotypes contribute significantly (P <0.0001) and substantially (49.1% of the explained variance) to the model, with the following corrected iCa means: ARQ/AGQ, 1.21 ± 0.01; ARQ/ARQ, 1.22 ± 0.01; ARQ/SRQ, 1.24 ± 0.01; SRQ/AGQ, 1.24 ± 0.03; SRQ/SRQ, 1.25 ± 0.01; ARQ/ARE, 1.25 ± 0.01; and SRQ/ARE, 1.27 ± 0.01. Our data confirm the association between iCa and the A986S locus and suggest that R990G and Q1011E are also predictive. Given the significant between-population variations in frequency of variant alleles in this CASR SNP cluster, tri-locus haplotyping may prove to be more informative in studies of association between variation in CASR and disease.

Original languageEnglish
Pages (from-to)5634-5638
Number of pages5
JournalJournal of Clinical Endocrinology and Metabolism
Volume89
Issue number11
DOIs
Publication statusPublished - Nov 2004

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Calcium-Sensing Receptors
Polymorphism
Blood
Calcium
Haplotypes
Single Nucleotide Polymorphism
Alleles
Genotype
Calcium Metabolism Disorders
Nucleotides
Blood Donors
Gene Frequency
Population
Metabolism
Regression analysis
Creatinine
Regression Analysis

ASJC Scopus subject areas

  • Biochemistry
  • Endocrinology, Diabetes and Metabolism

Cite this

Blood ionized calcium is associated with clustered polymorphisms in the carboxyl-terminal tail of the calcium-sensing receptor. / Scillitani, Alfredo; Guarnieri, Vito; De Geronimo, Simona; Muscarella, Lucia Anna; Battista, Claudia; D'Agruma, Leonardo; Bertoldo, Francesco; Florio, Cinzia; Minisola, Salvatore; Hendy, Geoffrey N.; Cole, David E C.

In: Journal of Clinical Endocrinology and Metabolism, Vol. 89, No. 11, 11.2004, p. 5634-5638.

Research output: Contribution to journalArticle

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title = "Blood ionized calcium is associated with clustered polymorphisms in the carboxyl-terminal tail of the calcium-sensing receptor",
abstract = "Blood ionized calcium (iCa) is a quantitative trait subject to genetic influence. iCa is maintained in a narrow range through the action of the calcium-sensing receptor (CASR) controlling PTH secretion and calcium excretion. A CASR single nucleotide polymorphism (SNP) prevalent in Caucasian populations (A986S) has shown significant association with iCa in a cohort of young women, but association with the neighboring SNPs, R990G and Q1011E, has not been examined. We studied 377 unrelated admits (184 men and 193 women) recruited as healthy adults from a blood donor clinic. The subjects were not taking any medications, nor did they have disorders of calcium metabolism. Relative frequencies for the CASR 986S, 990G, and 1011E minor alleles were 24{\%}, 4{\%}, and 3{\%} respectively. At the A986S locus, subjects with the AA genotype had significantly lower iCa (P = 0.0001) than subjects with one or two S alleles (mean ± SE, 1.221 ± 0.003 vs. 1.239 ± 0.003 mmol/liter). For the R990G site, subjects with the RR genotype had higher iCa than those with one copy of the 990G allele (1.230 ± 0.002 vs. 1.213 ± 0.007 mmol/liter; P = 0.032). With respect to the 1011 locus, iCa was lower in QQ genotype subjects than in the QE group (1.227 ± 0.002 vs. 1.255 ± 0.008 mmol/liter; P = 0.002). After resolution of phase for the doubly heterozygous subjects, analysis was conducted on haplotypes across all three loci. As expected, subjects with SRQ and ARE haplotypes are relatively hypercalcemic, and those with AGQ are hypocalcemic, relative to subjects with the common ARQ haplotype. Multiple regression analysis with clinical covariates (age, ses and menopausal status, creatinine, and PTH) showed that 16.5{\%} of the total variance in iCa may be explained, and the seven CASR haplotypes contribute significantly (P <0.0001) and substantially (49.1{\%} of the explained variance) to the model, with the following corrected iCa means: ARQ/AGQ, 1.21 ± 0.01; ARQ/ARQ, 1.22 ± 0.01; ARQ/SRQ, 1.24 ± 0.01; SRQ/AGQ, 1.24 ± 0.03; SRQ/SRQ, 1.25 ± 0.01; ARQ/ARE, 1.25 ± 0.01; and SRQ/ARE, 1.27 ± 0.01. Our data confirm the association between iCa and the A986S locus and suggest that R990G and Q1011E are also predictive. Given the significant between-population variations in frequency of variant alleles in this CASR SNP cluster, tri-locus haplotyping may prove to be more informative in studies of association between variation in CASR and disease.",
author = "Alfredo Scillitani and Vito Guarnieri and {De Geronimo}, Simona and Muscarella, {Lucia Anna} and Claudia Battista and Leonardo D'Agruma and Francesco Bertoldo and Cinzia Florio and Salvatore Minisola and Hendy, {Geoffrey N.} and Cole, {David E C}",
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T1 - Blood ionized calcium is associated with clustered polymorphisms in the carboxyl-terminal tail of the calcium-sensing receptor

AU - Scillitani, Alfredo

AU - Guarnieri, Vito

AU - De Geronimo, Simona

AU - Muscarella, Lucia Anna

AU - Battista, Claudia

AU - D'Agruma, Leonardo

AU - Bertoldo, Francesco

AU - Florio, Cinzia

AU - Minisola, Salvatore

AU - Hendy, Geoffrey N.

AU - Cole, David E C

PY - 2004/11

Y1 - 2004/11

N2 - Blood ionized calcium (iCa) is a quantitative trait subject to genetic influence. iCa is maintained in a narrow range through the action of the calcium-sensing receptor (CASR) controlling PTH secretion and calcium excretion. A CASR single nucleotide polymorphism (SNP) prevalent in Caucasian populations (A986S) has shown significant association with iCa in a cohort of young women, but association with the neighboring SNPs, R990G and Q1011E, has not been examined. We studied 377 unrelated admits (184 men and 193 women) recruited as healthy adults from a blood donor clinic. The subjects were not taking any medications, nor did they have disorders of calcium metabolism. Relative frequencies for the CASR 986S, 990G, and 1011E minor alleles were 24%, 4%, and 3% respectively. At the A986S locus, subjects with the AA genotype had significantly lower iCa (P = 0.0001) than subjects with one or two S alleles (mean ± SE, 1.221 ± 0.003 vs. 1.239 ± 0.003 mmol/liter). For the R990G site, subjects with the RR genotype had higher iCa than those with one copy of the 990G allele (1.230 ± 0.002 vs. 1.213 ± 0.007 mmol/liter; P = 0.032). With respect to the 1011 locus, iCa was lower in QQ genotype subjects than in the QE group (1.227 ± 0.002 vs. 1.255 ± 0.008 mmol/liter; P = 0.002). After resolution of phase for the doubly heterozygous subjects, analysis was conducted on haplotypes across all three loci. As expected, subjects with SRQ and ARE haplotypes are relatively hypercalcemic, and those with AGQ are hypocalcemic, relative to subjects with the common ARQ haplotype. Multiple regression analysis with clinical covariates (age, ses and menopausal status, creatinine, and PTH) showed that 16.5% of the total variance in iCa may be explained, and the seven CASR haplotypes contribute significantly (P <0.0001) and substantially (49.1% of the explained variance) to the model, with the following corrected iCa means: ARQ/AGQ, 1.21 ± 0.01; ARQ/ARQ, 1.22 ± 0.01; ARQ/SRQ, 1.24 ± 0.01; SRQ/AGQ, 1.24 ± 0.03; SRQ/SRQ, 1.25 ± 0.01; ARQ/ARE, 1.25 ± 0.01; and SRQ/ARE, 1.27 ± 0.01. Our data confirm the association between iCa and the A986S locus and suggest that R990G and Q1011E are also predictive. Given the significant between-population variations in frequency of variant alleles in this CASR SNP cluster, tri-locus haplotyping may prove to be more informative in studies of association between variation in CASR and disease.

AB - Blood ionized calcium (iCa) is a quantitative trait subject to genetic influence. iCa is maintained in a narrow range through the action of the calcium-sensing receptor (CASR) controlling PTH secretion and calcium excretion. A CASR single nucleotide polymorphism (SNP) prevalent in Caucasian populations (A986S) has shown significant association with iCa in a cohort of young women, but association with the neighboring SNPs, R990G and Q1011E, has not been examined. We studied 377 unrelated admits (184 men and 193 women) recruited as healthy adults from a blood donor clinic. The subjects were not taking any medications, nor did they have disorders of calcium metabolism. Relative frequencies for the CASR 986S, 990G, and 1011E minor alleles were 24%, 4%, and 3% respectively. At the A986S locus, subjects with the AA genotype had significantly lower iCa (P = 0.0001) than subjects with one or two S alleles (mean ± SE, 1.221 ± 0.003 vs. 1.239 ± 0.003 mmol/liter). For the R990G site, subjects with the RR genotype had higher iCa than those with one copy of the 990G allele (1.230 ± 0.002 vs. 1.213 ± 0.007 mmol/liter; P = 0.032). With respect to the 1011 locus, iCa was lower in QQ genotype subjects than in the QE group (1.227 ± 0.002 vs. 1.255 ± 0.008 mmol/liter; P = 0.002). After resolution of phase for the doubly heterozygous subjects, analysis was conducted on haplotypes across all three loci. As expected, subjects with SRQ and ARE haplotypes are relatively hypercalcemic, and those with AGQ are hypocalcemic, relative to subjects with the common ARQ haplotype. Multiple regression analysis with clinical covariates (age, ses and menopausal status, creatinine, and PTH) showed that 16.5% of the total variance in iCa may be explained, and the seven CASR haplotypes contribute significantly (P <0.0001) and substantially (49.1% of the explained variance) to the model, with the following corrected iCa means: ARQ/AGQ, 1.21 ± 0.01; ARQ/ARQ, 1.22 ± 0.01; ARQ/SRQ, 1.24 ± 0.01; SRQ/AGQ, 1.24 ± 0.03; SRQ/SRQ, 1.25 ± 0.01; ARQ/ARE, 1.25 ± 0.01; and SRQ/ARE, 1.27 ± 0.01. Our data confirm the association between iCa and the A986S locus and suggest that R990G and Q1011E are also predictive. Given the significant between-population variations in frequency of variant alleles in this CASR SNP cluster, tri-locus haplotyping may prove to be more informative in studies of association between variation in CASR and disease.

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