CYP3A5 基因多态性对异基因造血干细胞移植患者他克莫司血药浓度及不良事件的影响。

Effect of CYP3A5 Gene Polymorphisms on Tacrolimus Blood Concentrations and Adverse Events in Allogeneic Hematopoietic Stem Cell Transplant Patients.

机构信息

Department of Pharmacy, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital of Wannan Medical College), Wuhu, China.

出版信息

Transplant Proc. 2024 Sep;56(7):1678-1682. doi: 10.1016/j.transproceed.2024.08.012. Epub 2024 Aug 14.

DOI:10.1016/j.transproceed.2024.08.012

PMID:39147616

Abstract

BACKGROUND

Tacrolimus is the core basic immunosuppressant after transplantation. Cytochrome P450 3A5 (CYP3A5) is the main enzyme involved in tacrolimus metabolism, and rs776746A>G is the most frequently studied polymorphism in the CYP3A5 gene. The aim of this study was to investigate the effect of CYP3A5 gene polymorphisms on tacrolimus blood concentrations and acute graft versus host disease (GVHD) in patients with allogeneic hematopoietic stem cell transplantation (allo-HSCT).

METHODS

This study included adult patients who received allo-HSCT at the First Affiliated Hospital of Wannan Medical College from January 2021 to June 2022, and received postoperative treatment with tacrolimus. Tacrolimus blood levels were obtained by fully automatic chemiluminescence immunoassay analyzer. Polymerase chain reaction/restriction fragment length polymorphism was used to genotype for CYP3A5*3 allelic variants.

RESULTS

In a total of 50 transplant patients, 30 patients were detected with CYP3A5*3/3 genotype, 15 patients with CYP3A51/3 genotype, and 5 patients with CYP3A51/1 genotype. The initial tacrolimus blood concentrations in allo-HSCT patients with CYP3A51/*1, *1/*3, and *3/3 genes were 7.75, 8.61, and 10.19 ng/mL, respectively; The initial blood concentration/dose (C/D) ratios were 4.08, 4.42 and 5.66 ng/(mL·mg), respectively. The C/D ratios of allo-HSCT patients carrying CYP3A51/*1, *1/*3, and *3/3 genes were 4.35 and 4.71 and 5.58, 4.19, 4.56 and 5.71 ng/(mL·mg) in the second and 3rd weeks after operation. These results showed that the blood concentration and C/D ratio of tacrolimus in patients with CYP3A53/3 genotype were significantly higher than those in patients with CYP3A51/3 or CYP3A51/1 genotype. Moreover, the incidence of acute GVHD after allo-HSCT in patients with CYP3A51/1 genotype was significantly higher than that in patients with CYP3A51/3 or CYP3A53/*3 genotype.

CONCLUSIONS

Most patients carry the mutant allele CYP3A5*3. CYP3A5 gene polymorphisms affect tacrolimus blood concentrations and acute GVHD after allo-HSCT.

摘要

背景

他克莫司是移植术后的核心基础免疫抑制剂。细胞色素 P4503A5（CYP3A5）是他克莫司代谢中涉及的主要酶，rs776746A>G 是 CYP3A5 基因中最常研究的多态性。本研究旨在探讨 CYP3A5 基因多态性对异基因造血干细胞移植（allo-HSCT）患者他克莫司血药浓度和急性移植物抗宿主病（GVHD）的影响。

方法

本研究纳入了 2021 年 1 月至 2022 年 6 月在皖南医学院第一附属医院接受 allo-HSCT 的成年患者，并在术后接受他克莫司治疗。采用全自动化学发光免疫分析仪检测他克莫司血药浓度。聚合酶链反应/限制性片段长度多态性用于 CYP3A5*3 等位基因变异的基因分型。

结果

在总共 50 例移植患者中，30 例患者检测到 CYP3A5*3/3 基因型，15 例患者检测到 CYP3A51/3 基因型，5 例患者检测到 CYP3A51/1 基因型。allo-HSCT 患者 CYP3A51/*1、*1/*3 和 *3/3 基因的初始他克莫司血药浓度分别为 7.75、8.61 和 10.19ng/ml；初始血药浓度/剂量（C/D）比值分别为 4.08、4.42 和 5.66ng/（ml·mg）。携带 CYP3A51/*1、*1/*3 和 *3/3 基因的 allo-HSCT 患者在术后第 2 和第 3 周的 C/D 比值分别为 4.35、4.71 和 5.58、4.19、4.56 和 5.71ng/（ml·mg）。这些结果表明，CYP3A53/3 基因型患者的他克莫司血药浓度和 C/D 比值明显高于 CYP3A51/3 或 CYP3A51/1 基因型患者。此外，CYP3A51/1 基因型患者 allo-HSCT 后急性 GVHD 的发生率明显高于 CYP3A51/3 或 CYP3A53/*3 基因型患者。