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

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Abstract

Aims

Two single-nucleotide polymorphisms (SNPs) at the calcium-sensing receptor (CASR) gene were previously associated with kidney stones in patients with primary hyperparathyroidism (PHPT): rs1501899, likely associated with a decrease in CASR expression, and Arg990Gly, causing a gain of CASR function. To evaluate the interaction of these two SNPs in the stone risk, we tested the association of stones with the genotype at both SNPs in PHPT patients and the association of rs1501899 with CASR expression as messenger RNA (mRNA) in human kidney samples.

Methods and results

Two hundred and ninety-six PHPT patients were genotyped at the rs1501899 and Arg990Gly SNPs. Minor allele frequency at tested SNPs was higher in PHPT stone formers relative to non-stone forming patients. PHPT patients carrying one or two copies of the minor allele at both rs1501899 and Arg990Gly (n = 16) had the maximal risk of stones (odds ratio, OR 8.3) and higher serum ionized calcium compared with homozygous patients for the wild-type allele at both SNPs. CASR expression as mRNA was measured by real time polymerase chain reaction (PCR) in normal kidney medulla samples from 109 subjects. CASR mRNA was significantly lower in medulla samples from homozygotes for the minor allele at rs1501899 than in subjects with other genotypes.

Conclusions

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.

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Acknowledgments

Italian Ministry of University and Research (FIRST and Cofin 02).

Conflict of interest

None.

Author information

Authors and Affiliations

  1. Nephrology and Dialysis Unit, Postgraduate School of Nephrology, San Raffaele Scientific Institute, Vita Salute University, via Olgettina 60, 20132, Milan, Italy

    Giuseppe Vezzoli, Teresa Arcidiacono, Lorenza Macrina & Donatella Spotti

  2. Endocrinology Unit, IRCCS “Casa Sollievo della Sofferenza” Hospital, 71013, San Giovanni Rotondo, Foggia, Italy

    Alfredo Scillitani

  3. Endocrinology and Diabetology Unit, Department of Medical-Surgical Sciences, Policlinico San Donato IRCCS, Università degli Studi di Milano, 20097, San Donato, Milan, Italy

    Sabrina Corbetta

  4. Department of Medicine Surgery and Dentistry, Postgraduate School of Nephrology, Università degli Studi di Milano, 20122, Milan, Italy

    Annalisa Terranegra, Elena Dogliotti, Alessandra Mingione, Caterina Brasacchio, Daniele Cusi & Laura Soldati

  5. Genetics Unit, IRCCS Casa Sollievo della Sofferenza Hospital, 71013, San Giovanni Rotondo, Foggia, Italy

    Vito Guarnieri

  6. Endocrine Unit, Department of Medical Sciences, Fondazione Ospedale Maggiore Mangiagalli e Regina Elena IRCCS, Università degli Studi di Milano, 20122, Milan, Italy

    Cristina Eller-Vainicher & Anna Spada

  7. Pathobiology, Medicine and Genetics, University of Toronto, Toronto, ON, M5G1L5, Canada

    David E. C. Cole

  8. Department of Medicine, Physiology and Human Genetics, McGill University, Montreal, QC, H3A1A1, Canada

    Geoffrey N. Hendy

Authors
  1. Giuseppe Vezzoli
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  2. Alfredo Scillitani
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  3. Sabrina Corbetta
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  4. Annalisa Terranegra
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  5. Elena Dogliotti
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  6. Vito Guarnieri
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  7. Teresa Arcidiacono
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  8. Lorenza Macrina
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  9. Alessandra Mingione
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  10. Caterina Brasacchio
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  11. Cristina Eller-Vainicher
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  12. Daniele Cusi
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  13. Anna Spada
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  14. David E. C. Cole
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  15. Geoffrey N. Hendy
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  16. Donatella Spotti
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  17. Laura Soldati
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Corresponding author

Correspondence to Giuseppe Vezzoli.

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Vezzoli, G., Scillitani, A., Corbetta, S. et al. Risk of nephrolithiasis in primary hyperparathyroidism is associated with two polymorphisms of the calcium-sensing receptor gene. J Nephrol 28, 67–72 (2015). https://doi.org/10.1007/s40620-014-0106-8

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  • DOI: https://doi.org/10.1007/s40620-014-0106-8

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