肾移植患者队列中药物遗传学与长期临床进展的关联。
Pharmacogenetics association with long-term clinical evolution in a kidney transplant patients cohort.
作者信息
Sendra Luis, Olivera-Pasquini Gladys G, Zucchet Enrique G, Genvigir Fabiana D V, Beneyto María Isabel, Hernández-Jaras Julio, Herrero María José, Aliño Salvador F
机构信息
Gene Therapy and Pharmacogenomics, Department of Pharmacology, University of Valencia, 46010, Valencia, Spain.
Pharmacogenetics and Gene Therapy Unit, La Fe Health Research Institute, 46026, Valencia, Spain.
出版信息
Curr Res Pharmacol Drug Discov. 2025 Jul 24;9:100230. doi: 10.1016/j.crphar.2025.100230. eCollection 2025.
BACKGROUND
Pharmacogenetic variability has been reported to influence the efficacy and safety of immunosuppressive therapies in early stages of kidney transplantation. This study investigates long-term associations between pharmacogene variants and clinical outcomes in a cohort of kidney transplant recipients over a 12-year follow-up.
MATERIALS AND METHODS
We analyzed 37 SNPs from 14 genes related to drug metabolism and transport in 79 kidney transplant patients. Clinical parameters, including survival, renal function, tumor occurrence, and pharmacokinetics of tacrolimus, were evaluated. Logistic regression and Kaplan-Meier analyses assessed associations between gene variants and clinical outcomes.
RESULTS
Variants in metabolizer (CYP3A5, CYP2B6) and transporter genes (ABCB1, ABCC2) were associated with 12-year survival. Increased tumor risk correlated with ABCC2 variants in donors and decreased risk with CYP2B6 rs3745274 in recipients. Renal function was influenced by variants in ABCB1, ABCC2, CYP3A5, CYP3A4, and CYP2B6. Tacrolimus dose-dependent concentration was affected by variants in CYP3A4, CYP3A5, CYP2C19, ABCB1, and SLCO1B1. Increased nephrotoxicity risk was associated with CYP2C19 rs4244285 and reduced by SLCO1B1 rs2306283 AA and AG variants. Gene variant interactions between metabolizer and transporter genes were also associated with altered risk of events incidence.
DISCUSSION
Our findings support that pharmacogene variants influence transplant outcomes. Notable associations include survival related to ABCB1 and ABCC2 variants, tumor occurrence linked to CYP2B6 rs3745274, and renal function affected by multiple pharmacogenes. Variants in CYP2C19 and SLCO1B1 significantly impacted tacrolimus pharmacokinetics and nephrotoxicity risk. These results underline the importance of pharmacogenetic testing for personalized management in kidney transplantation, although further validation in larger cohorts is necessary.
背景
据报道，药物遗传学变异性会影响肾移植早期免疫抑制治疗的疗效和安全性。本研究调查了一组肾移植受者在12年随访期间药物基因变异与临床结局之间的长期关联。
材料与方法
我们分析了79例肾移植患者中14个与药物代谢和转运相关基因的37个单核苷酸多态性（SNP）。评估了包括生存、肾功能、肿瘤发生以及他克莫司药代动力学在内的临床参数。逻辑回归和Kaplan-Meier分析评估了基因变异与临床结局之间的关联。
结果
代谢酶（CYP3A5、CYP2B6）和转运蛋白基因（ABCB1、ABCC2）的变异与12年生存率相关。供体中ABCC2变异与肿瘤风险增加相关，而受体中CYP2B6 rs3745274与肿瘤风险降低相关。肾功能受ABCB1、ABCC2、CYP3A5、CYP3A4和CYP2B6变异的影响。他克莫司剂量依赖性浓度受CYP3A4、CYP3A5、CYP2C19、ABCB1和SLCO1B1变异的影响。肾毒性风险增加与CYP2C19 rs4244285相关，而SLCO1B1 rs2306283的AA和AG变异可降低肾毒性风险。代谢酶和转运蛋白基因之间的基因变异相互作用也与事件发生率风险的改变相关。
讨论
我们的研究结果支持药物基因变异会影响移植结局。显著的关联包括与ABCB1和ABCC2变异相关的生存、与CYP2B6 rs3745274相关的肿瘤发生以及受多种药物基因影响的肾功能。CYP2C19和SLCO1B1变异显著影响他克莫司的药代动力学和肾毒性风险。这些结果强调了药物遗传学检测在肾移植个性化管理中的重要性，尽管需要在更大的队列中进行进一步验证。
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