Calcium-Sensing Receptor Genotype and Response to Cinacalcet in Patients Undergoing Hemodialysis

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.

Keywords: Alkaline Phosphatase; Alleles; Chronic Kidney Disease-Mineral and Bone Disorder; Cinacalcet Hydrochloride; DNA; FGF23; Genotype; Humans; Linkage Disequilibrium; Minerals; Polymorphism, Single Nucleotide; Receptors, Calcium-Sensing; calcium; calcium sensing receptor; fracture; human genetics; parathyroid hormone; renal dialysis; single nucleotide polymorphisms.

Figure 1.

Linkage disequilibrium (LD) maps for the calcium-sensing receptor (CASR). LD maps for the CASR single nucleotide polymorphisms (SNPs) examined in (A) the European ancestry population and (B) the African ancestry population. Numeric values represent pairwise LD as measured by r². SNPs in high LD are represented by darker squares.

Figure 2.

Association of CASR SNPs and percent change in biochemical measures from baseline to week 20. (A) Association of the CASR SNP rs937627 with percent change in PTH in the EA population, adjusted for baseline PTH, and age, demonstrating an association with genotype (P<0.05) but no interaction with treatment (P=0.06). (B) Association of the CASR SNP rs2036399 with percent change in FGF23 in the AfAn population, adjusted for baseline FGF23 and age. The results demonstrate no association with genotype (P=0.34) but an interaction with treatment (P<0.02). Homozygotes for the minor allele had a greater reduction in FGF23 with cinacalcet. (C) EA population and (D) AfAn population association of the CASR SNP rs9740 with percent change in calcium adjusted for age, baseline calcium, duration dialysis, baseline bone alkaline phosphatase in EA, and baseline calcium and age in AfAn. In the EA population, there was no association with genotype (P=0.89), but there was a treatment-by-genotype interaction in that homozygotes for the major allele had a greater decrease in response to cinacalcet (P=0.03). In the AfAn population, there was no main effect of genotype (P=0.06) but a treatment-by-genotype interaction (P=0.02). Gray bars. Genotype; Black bars, participants in the EVOLVE trial randomized to placebo; hashed bars, participants in the EVOLVE trial randomized to cinacalcet. AfAn, African ancestry; CASR, calcium-sensing receptor; EA, European ancestry; EVOLVE, Evaluation of Cinacalcet HCl Therapy to Lower Cardiovascular Events; FGF23, fibroblast growth factor 23; PTH, parathyroid hormone; SNP, single nucleotide polymorphism.

Figure 3.

Association of CASR SNP rs7647446 with incidence of fracture during the Evaluation of Cinacalcet HCl Therapy to Lower Cardiovascular Events (EVOLVE) trial. Association of genotype and genotype-by-treatment interaction and any type of fracture during the EVOLVE trial. The results demonstrate that there is a modest but nonsignificant increased association with a higher incidence of fracture with increased number of minor A alleles (P=0.08), and that the number of fractures is reduced when the individuals are treated with cinacalcet (P=0.03). Similar results were observed with other single nucleotide polymorphism in high linkage disequilibrium with rs7647446. Gray bars, genotype; black bars, participants in the EVOLVE trial randomized to placebo; hashed bars, participants in the EVOLVE trial randomized to cinacalcet.