CYP3A4/5基因评分和ABCB1基因多态性对巴西肾移植患者他克莫司血药浓度及肾功能的影响。

Influence of the CYP3A4/5 genetic score and ABCB1 polymorphisms on tacrolimus exposure and renal function in Brazilian kidney transplant patients.

作者信息

Genvigir Fabiana D V, Salgado Patricia C, Felipe Claudia R, Luo Elena Y F, Alves Camila, Cerda Alvaro, Tedesco-Silva Helio, Medina-Pestana Jose O, Oliveira Nagilla, Rodrigues Alice C, Doi Sonia Q, Hirata Mario H, Hirata Rosario D C

机构信息

aDepartment of Clinical and Toxicological Analysis, School of Pharmaceutical Sciences bDepartment of Pharmacology, Institute of Biomedical Sciences, University of Sao Paulo cNephrology Division, Hospital do Rim, Universidade Federal de São Paulo, Sao Paulo, Brazil dCenter of Molecular Biology and Pharmacogenetics, BIOREN-CEGIN, Universidad de La Frontera, Temuco, Chile eSchool of Medicine, Uniformed Services University, Bethesda, Maryland, USA.

出版信息

Pharmacogenet Genomics. 2016 Oct;26(10):462-72. doi: 10.1097/FPC.0000000000000237.

DOI:10.1097/FPC.0000000000000237

PMID:27434656

Abstract

BACKGROUND

Polymorphisms in genes encoding transport proteins and metabolizing enzymes involved in tacrolimus (TAC) disposition may be important sources of individual variability during treatment.

OBJECTIVE

The aim of this study was to investigate the effect of combined CYP3A4 and CYP3A5 variants, using a CYP3A4/5 genetic score, and ABCB1 polymorphisms on therapeutic TAC monitoring and their relationship with clinical outcomes.

MATERIAL AND METHODS

Brazilian kidney transplant recipients (n=151), who received TAC over 3 months after transplantation, were genotyped for CYP3A4 rs2242480 (g.20230G>A), CYP3A5 rs15524 (g.31611C>T) and rs776746 (g.6986A>G), ABCB1 rs1128503 (c.1236C>T), rs1045642 (c.3435C>T), and rs2032582 (c.2677G>T/A) polymorphisms.

RESULTS

Frequencies of CYP3A4 g.20230A, CYP3A5 g.31611C, and g.6986A were 0.37, 0.26, and 0.28, respectively. These alleles were associated with TAC rapid metabolization and were used for CYP3A4/5 genetic score construction. A higher CYP3A4/5 genetic score was associated with higher TAC dose and lower concentrations for dose administered (Co/D, P<0.05). Ninety days after transplantation, the presence of two or more rapid metabolization alleles contributed toward 27.7% of Co/D variability and was associated with a lower estimated glomerular filtration rate values (P<0.05). For ABCB1, the frequencies of c.1236T, c.3435T, and c.2677T/A alleles were 0.42, 0.42, and 0.33/0.04. At 30 days after transplantation, patients carrying ABCB1 c.1236TT+c.3435TT+(c.2677TT+TA) genotypes had higher TAC Co/D than those with common or heterozygous genotypes (P<0.05).

CONCLUSION

The results show the impact of the CYP3A4/5 genetic score on TAC exposure and renal function in Brazilian patients. Furthermore, ABCB1 polymorphisms, in a combined analysis, influenced TAC Co/D at 30 days after transplantation.

摘要

背景

编码参与他克莫司（TAC）处置的转运蛋白和代谢酶的基因多态性可能是治疗期间个体差异的重要来源。

目的

本研究旨在使用CYP3A4/5基因评分研究CYP3A4和CYP3A5联合变异以及ABCB1多态性对治疗性TAC监测的影响及其与临床结局的关系。

材料与方法

对151例巴西肾移植受者进行基因分型，这些受者在移植后3个月以上接受TAC治疗，检测CYP3A4 rs2242480（g.20230G>A）、CYP3A5 rs15524（g.31611C>T）和rs776746（g.6986A>G）、ABCB1 rs1128503（c.1236C>T）、rs1045642（c.3435C>T）以及rs2032582（c.2677G>T/A）多态性。

结果

CYP3A4 g.20230A、CYP3A5 g.31611C和g.6986A的频率分别为0.37、0.26和0.28。这些等位基因与TAC快速代谢相关，并用于构建CYP3A4/5基因评分。较高的CYP3A4/5基因评分与较高的TAC剂量和较低的给药剂量浓度（Co/D，P<0.05）相关。移植后90天，两个或更多快速代谢等位基因的存在导致Co/D变异性的27.7%，并与较低的估计肾小球滤过率值相关（P<0.05）。对于ABCB1，c.1236T、c.3435T和c.2677T/A等位基因的频率分别为0.42、0.42和0.33/0.04。移植后30天，携带ABCB1 c.1236TT + c.3435TT +（c.2677TT + TA）基因型的患者的TAC Co/D高于具有常见或杂合基因型的患者（P<0.05）。