Discipline of Pharmacology, Adelaide Medical School, University of Adelaide.
Department of Pharmacology, Queen Elizabeth Hospital.
Pharmacogenet Genomics. 2019 Jan;29(1):9-17. doi: 10.1097/FPC.0000000000000360.
CYP3A4/5 and P-glycoprotein (P-gp, ABCB1) affect tacrolimus (TAC) exposure in T cells and kidney cells. Genetic variability of these genes has been widely studied for effects on acute rejection and kidney function after transplantation, but findings remain contradictory. In addition, cytochrome P450 reductase (POR) is important for CYP3A4/5 activity, and the pregnane X receptor (NR1I2) regulates CYP3A4/5 and P-gp expression. However, the relationship between POR and NR1I2 genetics and acute rejection and kidney function has not been extensively investigated.
The aim of this study was to investigate the effect of ABCB1 (61A>G, 1199G>A, 1236C>T, 2677G>T, 3435C>T), CYP3A422, CYP3A53, NR1I2 (8055C>T, 63396C>T) and POR*28 genotypes/haplotypes on acute rejection and kidney function in the first 3 months after transplant.
The study included 165 kidney transplant recipients, who received TAC, mycophenolate and prednisolone, and 129 donors. TAC dose was adjusted to target trough blood concentrations of 8-15 ng/ml by therapeutic drug monitoring. Recipient and donor genotype/haplotype differences in acute rejection incidence within the first 2 weeks after transplant were assessed by logistic regression, adjusting for induction therapy, human leucocyte antigen mismatches, kidney transplant number, peak panel-reactive antibodies and donor type. Recipient and donor genotype/haplotype differences in estimated glomerular filtration rate in the first 3 months after transplant were assessed by linear mixed effects analysis, adjusting for acute rejection, delayed graft function and donor type.
No genetic factors significantly affected acute rejection or estimated glomerular filtration rate after correction for multiple comparisons (P>0.004).
Recipient and donor dispositional genetics had no significant effect on short-term clinical outcomes in kidney transplant patients receiving TAC therapeutic drug monitoring.
CYP3A4/5 和 P-糖蛋白（P-gp，ABCB1）会影响 T 细胞和肾脏细胞中的他克莫司（TAC）暴露。这些基因的遗传多态性已广泛研究过其对移植后急性排斥反应和肾功能的影响，但研究结果仍存在矛盾。此外，细胞色素 P450 还原酶（POR）对 CYP3A4/5 活性很重要，而孕烷 X 受体（NR1I2）调节 CYP3A4/5 和 P-gp 的表达。然而，POR 和 NR1I2 遗传与急性排斥反应和肾功能之间的关系尚未得到广泛研究。
本研究旨在探讨 ABCB1（61A>G、1199G>A、1236C>T、2677G>T、3435C>T）、CYP3A422、CYP3A53、NR1I2（8055C>T、63396C>T）和 POR*28 基因型/单倍型对移植后 3 个月内急性排斥反应和肾功能的影响。
该研究纳入了 165 例接受他克莫司、霉酚酸酯和泼尼松龙治疗的肾移植受者和 129 名供者。通过治疗药物监测调整他克莫司的剂量，以达到目标血药谷浓度 8-15ng/ml。通过逻辑回归评估移植后 2 周内急性排斥反应发生率的受者和供者基因型/单倍型差异，调整诱导治疗、人类白细胞抗原错配、肾移植数量、峰值 panel-reactive 抗体和供者类型。通过线性混合效应分析评估移植后 3 个月内估算肾小球滤过率的受者和供者基因型/单倍型差异，调整急性排斥反应、延迟移植物功能和供者类型。
在进行多次比较校正后，没有遗传因素显著影响急性排斥反应或估算肾小球滤过率（P>0.004）。
在接受他克莫司治疗药物监测的肾移植患者中，受者和供者处置遗传因素对短期临床结局无显著影响。
