Associations of ABCB1, NFKB1, CYP3A, and NR1I2 polymorphisms with cyclosporine trough concentrations in Chinese renal transplant recipients
Abstract
Yu ZHANG1, #, Jia-li LI1, #, Qian FU2, Xue-ding WANG1, Long-shan LIU2, Chang-xi WANG2, *, Wen XIE3, Zhuo-jia CHEN1, Wen-ying SHU1, Min HUANG1, *
1Institute of Clinical Pharmacology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China; 2Kidney Transplant Department, Transplant Center, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China; 3Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA 15261, USA
Aim: Cyclosporine requires close therapeutic drug monitoring because of its narrow therapeutic index and marked inter-individual pharmacokinetic variation. In this study, we investigated the associations of CYP3A4, CYP3A5, ABCB1, NFKB1, and NR1I2 polymorphisms with cyclosporine concentrations in Chinese renal transplant recipients in the early period after renal transplantation.
Methods: A total of 101 renal transplant recipients receiving cyclosporine were genotyped for CYP3A4*1G, CYP3A5*3, ABCB1 C1236T, G2677T/A, C3435T, NFKB1 -94 ins/del ATTG, and NR1I2 polymorphisms. Cyclosporine whole blood levels were measured by a fluorescence polarization immunoassay. Trough concentrations of cyclosporine were determined for days 7-18 following transplantation.
Results: The dose-adjusted trough concentration (C0) of cyclosporine in ABCB1 2677 TT carriers was significantly higher than that in GG carriers together with GT carriers [90.4±24.5 vs 67.8±26.8 (ng/mL)/(mg/kg), P=0.001]. ABCB1 3435 TT carriers had a significantly higher dose-adjusted C0 of cyclosporine than CC carriers together with CT carriers [92.0±24.0 vs 68.4±26.5 (ng/mL)/(mg/kg), P=0.002]. Carriers of the ABCB1 1236TT-2677TT-3435TT haplotype had a considerably higher CsA C0/D than carriers of other genotypes [97.2±21.8 vs 68.7±26.9 (ng/mL)/(mg/kg), P=0.001]. Among non-carriers of the ABCB1 2677 TT and 3435 TT genotypes, patients with the NFKB1 -94 ATTG ins/ins genotype had a significantly higher dose-adjusted C0 than those with the -94 ATTG del/del genotype [75.9±32.9 vs 55.1±15.1 (ng/mL)/(mg/kg), P=0.026].
Conclusion: These results illustrate that the ABCB1 and NFKB1 genotypes are closely correlated with cyclosporine trough concentrations, suggesting that these SNPs are useful for determining the appropriate dose of cyclosporine.
Keywords: cyclosporine; ABCB1; NFKB1; NR1I2; CYP3A; genetic polymorphism
We appreciate the financial support provided by a National Science and Technology Major Project in Science and Technology grant from the Science and Technology Ministry of China (Grant No 2012ZX09506001-004), National Natural Science Foundations of China (No 81102515, 81072708, and 81173131) and Medical Research Foundation of Guangdong Province (No B2011067).
# These authors contributed equally to this work.
* To whom correspondence should be addressed.
E-mail huangmin@mail.sysu.edu.cn (Min HUANG); cx6363@163.com (Chang-xi WANG)
Received 2012-11-23 Accepted 2012-12-20
Keywords:
1Institute of Clinical Pharmacology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China; 2Kidney Transplant Department, Transplant Center, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China; 3Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA 15261, USA
Aim: Cyclosporine requires close therapeutic drug monitoring because of its narrow therapeutic index and marked inter-individual pharmacokinetic variation. In this study, we investigated the associations of CYP3A4, CYP3A5, ABCB1, NFKB1, and NR1I2 polymorphisms with cyclosporine concentrations in Chinese renal transplant recipients in the early period after renal transplantation.
Methods: A total of 101 renal transplant recipients receiving cyclosporine were genotyped for CYP3A4*1G, CYP3A5*3, ABCB1 C1236T, G2677T/A, C3435T, NFKB1 -94 ins/del ATTG, and NR1I2 polymorphisms. Cyclosporine whole blood levels were measured by a fluorescence polarization immunoassay. Trough concentrations of cyclosporine were determined for days 7-18 following transplantation.
Results: The dose-adjusted trough concentration (C0) of cyclosporine in ABCB1 2677 TT carriers was significantly higher than that in GG carriers together with GT carriers [90.4±24.5 vs 67.8±26.8 (ng/mL)/(mg/kg), P=0.001]. ABCB1 3435 TT carriers had a significantly higher dose-adjusted C0 of cyclosporine than CC carriers together with CT carriers [92.0±24.0 vs 68.4±26.5 (ng/mL)/(mg/kg), P=0.002]. Carriers of the ABCB1 1236TT-2677TT-3435TT haplotype had a considerably higher CsA C0/D than carriers of other genotypes [97.2±21.8 vs 68.7±26.9 (ng/mL)/(mg/kg), P=0.001]. Among non-carriers of the ABCB1 2677 TT and 3435 TT genotypes, patients with the NFKB1 -94 ATTG ins/ins genotype had a significantly higher dose-adjusted C0 than those with the -94 ATTG del/del genotype [75.9±32.9 vs 55.1±15.1 (ng/mL)/(mg/kg), P=0.026].
Conclusion: These results illustrate that the ABCB1 and NFKB1 genotypes are closely correlated with cyclosporine trough concentrations, suggesting that these SNPs are useful for determining the appropriate dose of cyclosporine.
Keywords: cyclosporine; ABCB1; NFKB1; NR1I2; CYP3A; genetic polymorphism
We appreciate the financial support provided by a National Science and Technology Major Project in Science and Technology grant from the Science and Technology Ministry of China (Grant No 2012ZX09506001-004), National Natural Science Foundations of China (No 81102515, 81072708, and 81173131) and Medical Research Foundation of Guangdong Province (No B2011067).
# These authors contributed equally to this work.
* To whom correspondence should be addressed.
E-mail huangmin@mail.sysu.edu.cn (Min HUANG); cx6363@163.com (Chang-xi WANG)
Received 2012-11-23 Accepted 2012-12-20