Calcium-sensing receptor genotype and response to cinacalcet in patients undergoing hemodialysis

Sharon Moe, Leah Wetherill, Brian Decker, Dongbing Lai, Safa Abdalla, Jin Long, Matteo Vatta, Tatiana Foroud, Glenn M. Chertow

Research output: Contribution to journalArticle

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Abstract

Background and objectives We tested the hypothesis that single nucleotide polymorphisms (SNPs) in the calcium-sensing receptor (CASR) alter the response to the calcimimetic cinacalcet. Design, setting, participants, & measurements We analyzed DNA samples in the Evaluation of Cinacalcet HCl Therapy to Lower Cardiovascular Events (EVOLVE) trial, a randomized trial comparing cinacalcet to placebo on a background of usual care. Of the 3883 patients randomized, 1919 (49%) consented to DNA collection, and samples from 1852 participants were genotyped for 18 CASR polymorphisms. The European ancestry (EA; n=1067) and African ancestry (AfAn; n=405) groups were assessed separately. SNPs in CASR were tested for their association with biochemical measures of mineral metabolism at baseline, percent change from baseline to 20 weeks, and risk of clinical fracture as dependent variables. Results There were modest associations of CASR SNPs with increased baseline serum parathyroid hormone and bone alkaline phosphatase primarily with the minor allele in the EA group (all P≤0.03), but not in the AfAn sample. In contrast, there was a modest association of decreased baseline serum calcium and FGF23 with CASR SNPs (P=0.04) primarily with the minor allele in the AfAn but not in the EA sample. The minor allele of two SNPs was associated with decreased percent reduction in parathyroid hormone from baseline to 20 weeks in the EA population (P<0.04) and this was not altered with cinacalcet. In both EA and AfAn, the same SNP (rs9740) was associated with decreased calcium with cinacalcet treatment (EA and AfAn P≤0.03). Three SNPs in high linkage disequilibrium were associated with a higher risk of clinical fracture that was attenuated by cinacalcet treatment in the EA sample (P<0.04). Conclusions These modest associations, if validated, may provide explanations for differences in CKD–mineral bone disorder observed in EA and AfAn populations, and for differential biochemical responses to calcimimetics.

Original languageEnglish (US)
Pages (from-to)1128-1138
Number of pages11
JournalClinical Journal of the American Society of Nephrology
Volume12
Issue number7
DOIs
StatePublished - Jul 7 2017

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Calcium-Sensing Receptors
Single Nucleotide Polymorphism
Renal Dialysis
Genotype
Alleles
Parathyroid Hormone
Calcium
Bone and Bones
DNA
Linkage Disequilibrium
Cinacalcet Hydrochloride
Serum
Population
Minerals
Alkaline Phosphatase
Therapeutics
Placebos

Keywords

  • Alkaline Phosphatase
  • Alleles
  • Calcium
  • Calcium sensing receptor
  • Chronic Kidney Disease-Mineral and Bone Disorder
  • Cinacalcet Hydrochloride
  • DNA
  • FGF23
  • Fracture
  • Genotype
  • Human genetics
  • Humans
  • Linkage Disequilibrium
  • Minerals
  • Parathyroid hormone
  • Polymorphism, Single Nucleotide
  • Receptors, Calcium-Sensing
  • Renal dialysis
  • Single nucleotide polymorphisms

ASJC Scopus subject areas

  • Epidemiology
  • Critical Care and Intensive Care Medicine
  • Nephrology
  • Transplantation

Cite this

Calcium-sensing receptor genotype and response to cinacalcet in patients undergoing hemodialysis. / Moe, Sharon; Wetherill, Leah; Decker, Brian; Lai, Dongbing; Abdalla, Safa; Long, Jin; Vatta, Matteo; Foroud, Tatiana; Chertow, Glenn M.

In: Clinical Journal of the American Society of Nephrology, Vol. 12, No. 7, 07.07.2017, p. 1128-1138.

Research output: Contribution to journalArticle

Moe, Sharon ; Wetherill, Leah ; Decker, Brian ; Lai, Dongbing ; Abdalla, Safa ; Long, Jin ; Vatta, Matteo ; Foroud, Tatiana ; Chertow, Glenn M. / Calcium-sensing receptor genotype and response to cinacalcet in patients undergoing hemodialysis. In: Clinical Journal of the American Society of Nephrology. 2017 ; Vol. 12, No. 7. pp. 1128-1138.
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abstract = "Background and objectives We tested the hypothesis that single nucleotide polymorphisms (SNPs) in the calcium-sensing receptor (CASR) alter the response to the calcimimetic cinacalcet. Design, setting, participants, & measurements We analyzed DNA samples in the Evaluation of Cinacalcet HCl Therapy to Lower Cardiovascular Events (EVOLVE) trial, a randomized trial comparing cinacalcet to placebo on a background of usual care. Of the 3883 patients randomized, 1919 (49{\%}) consented to DNA collection, and samples from 1852 participants were genotyped for 18 CASR polymorphisms. The European ancestry (EA; n=1067) and African ancestry (AfAn; n=405) groups were assessed separately. SNPs in CASR were tested for their association with biochemical measures of mineral metabolism at baseline, percent change from baseline to 20 weeks, and risk of clinical fracture as dependent variables. Results There were modest associations of CASR SNPs with increased baseline serum parathyroid hormone and bone alkaline phosphatase primarily with the minor allele in the EA group (all P≤0.03), but not in the AfAn sample. In contrast, there was a modest association of decreased baseline serum calcium and FGF23 with CASR SNPs (P=0.04) primarily with the minor allele in the AfAn but not in the EA sample. The minor allele of two SNPs was associated with decreased percent reduction in parathyroid hormone from baseline to 20 weeks in the EA population (P<0.04) and this was not altered with cinacalcet. In both EA and AfAn, the same SNP (rs9740) was associated with decreased calcium with cinacalcet treatment (EA and AfAn P≤0.03). Three SNPs in high linkage disequilibrium were associated with a higher risk of clinical fracture that was attenuated by cinacalcet treatment in the EA sample (P<0.04). Conclusions These modest associations, if validated, may provide explanations for differences in CKD–mineral bone disorder observed in EA and AfAn populations, and for differential biochemical responses to calcimimetics.",
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AU - Vatta, Matteo

AU - Foroud, Tatiana

AU - Chertow, Glenn M.

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N2 - Background and objectives We tested the hypothesis that single nucleotide polymorphisms (SNPs) in the calcium-sensing receptor (CASR) alter the response to the calcimimetic cinacalcet. Design, setting, participants, & measurements We analyzed DNA samples in the Evaluation of Cinacalcet HCl Therapy to Lower Cardiovascular Events (EVOLVE) trial, a randomized trial comparing cinacalcet to placebo on a background of usual care. Of the 3883 patients randomized, 1919 (49%) consented to DNA collection, and samples from 1852 participants were genotyped for 18 CASR polymorphisms. The European ancestry (EA; n=1067) and African ancestry (AfAn; n=405) groups were assessed separately. SNPs in CASR were tested for their association with biochemical measures of mineral metabolism at baseline, percent change from baseline to 20 weeks, and risk of clinical fracture as dependent variables. Results There were modest associations of CASR SNPs with increased baseline serum parathyroid hormone and bone alkaline phosphatase primarily with the minor allele in the EA group (all P≤0.03), but not in the AfAn sample. In contrast, there was a modest association of decreased baseline serum calcium and FGF23 with CASR SNPs (P=0.04) primarily with the minor allele in the AfAn but not in the EA sample. The minor allele of two SNPs was associated with decreased percent reduction in parathyroid hormone from baseline to 20 weeks in the EA population (P<0.04) and this was not altered with cinacalcet. In both EA and AfAn, the same SNP (rs9740) was associated with decreased calcium with cinacalcet treatment (EA and AfAn P≤0.03). Three SNPs in high linkage disequilibrium were associated with a higher risk of clinical fracture that was attenuated by cinacalcet treatment in the EA sample (P<0.04). Conclusions These modest associations, if validated, may provide explanations for differences in CKD–mineral bone disorder observed in EA and AfAn populations, and for differential biochemical responses to calcimimetics.

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KW - Polymorphism, Single Nucleotide

KW - Receptors, Calcium-Sensing

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