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Pharmacogenetic analysis of cinacalcet response in secondary hyperparathyroidism patients

Authors Jeong S, Kim I, Oh K, Han N, Joo KW, Kim HJ, Oh J

Received 30 December 2015

Accepted for publication 1 March 2016

Published 8 July 2016 Volume 2016:10 Pages 2211—2225

DOI https://doi.org/10.2147/DDDT.S103370

Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Lucy Goodman

Peer reviewer comments 3

Editor who approved publication: Prof. Dr. Wei Duan


Sohyun Jeong,1 In-Wha Kim,1 Kook-Hwan Oh,2 Nayoung Han,1 Kwon Wook Joo,2 Hyo Jin Kim,2 Jung Mi Oh1

1College of Pharmacy, Research Institute of Pharmaceutical Sciences, Seoul National University, 2Department of Internal Medicine, Division of Nephrology, Seoul National University Hospital, Seoul, Korea

Background:
Secondary hyperparathyroidism (SHPT) is one of the major risk factors of morbidity and mortality in end-stage renal disease. Cinacalcet effectively controls SHPT without causing hypercalcemia and hyperphosphatemia. However, there is significant inter-individual response variance to cinacalcet treatment. Therefore, we aimed to evaluate the genetic effects related with parathyroid hormone regulation as factors for cinacalcet response variance.
Methods: Patients with a diagnosis of SHPT based on intact parathyroid hormone (iPTH) >300 pg/mL on dialysis were included in this study. They were over 18 years and have been treated by cinacalcet for more than 3 months. Responders and nonresponders were grouped by the serum iPTH changes. Twenty-four single nucleotide polymorphisms of CASR, VDR, FGFR1, KL, ALPL, RGS14, NR4A2, and PTHLH genes were selected for the pharmacogenetic analysis.
Results: After adjusting for age, sex, and calcium level, CASR rs1042636 (odds ratio [OR]: 0.066, P=0.027) and rs1802757 (OR: 10.532, P=0.042) were associated with cinacalcet response. The association of haplotypes of CASR rs1042636, rs10190, and rs1802757; GCC (OR: 0.355, P=0.015); and ATT (OR: 2.769, P=0.014) with cinacalcet response was also significant.
Conclusion:
We obtained supporting information of the associations between cinacalcet response and CASR polymorphisms. CASR single nucleotide polymorphisms (SNPs) rs1802757, rs1042636, and haplotypes of rs1042636, rs10190, and rs1802757 were significantly associated with cinacalcet response variance.

Keywords: CASR, calcium sensing receptor, SHPT, genetic polymorphisms, haplotype, single nucleotide polymorphisms

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