Department of Clinical Chemistry, Erasmus MC, Rotterdam, The Netherlands.
Pharmacogenet Genomics. 2012 May;22(5):373-80. doi: 10.1097/FPC.0b013e328351f3c1.
Cyclosporine A (CsA) is a substrate of cytochrome P450 3A4 (CYP3A4). Recently, a newly discovered intron 6 single-nucleotide polymorphism in CYP3A4 (rs35599367 C>T), defining the CYP3A4*22 allele, has been linked to reduced hepatic expression and activity of CYP3A4. In the present study, the clinical impact of this single-nucleotide polymorphism was investigated in a cohort of patients receiving a CsA-based immunosuppressive regimen.
A total of 172 de-novo kidney transplant recipients, receiving CsA/mycophenolate mofetil as immunosuppressive therapy and participating in the Fixed-Dose Concentration Controlled study, were genotyped for the new CYP3A4*22 allele. CsA C(0) and/or C(2) levels were measured on days 3 and 10 and in months 1, 3, 6, and 12 after transplantation. Plasma creatinine concentrations, delayed graft function (DGF), and biopsy-proven acute rejection were recorded.
The CYP3A422 allele was significantly associated with a higher risk of DGF compared with the CYP3A41/1 patients after adjustment for known risk factors [odds ratio (OR)=6.34, confidence interval (CI(95%): 1.38-29.3), P=0.015]. Mixed-model analysis demonstrated that the overall creatinine clearance was 20% lower in CYP3A422 allele carriers compared with CYP3A4*1/*1 patients [CI(95%) (-33.1 to -7.2%), P=0.002]. For ABCB1 3435C>T, T-variant carriers had a decreased risk of developing DGF compared with CC patients [CT: OR=0.30, CI(95%) (0.11-0.77), P=0.011; TT: OR=0.18, CI(95%) (0.05-0.67), P=0.011].
CYP3A422 constitutes a risk factor for DGF and worse creatinine clearance in patients receiving CsA-based immunosuppressive therapy. Therefore, pretransplant genotyping for the CYP3A422 allele might help clinicians to identify patients at risk of DGF and poor renal function when treated with CsA.
环孢素 A（CsA）是细胞色素 P450 3A4（CYP3A4）的底物。最近，在 CYP3A4 中发现了一个新的内含子 6 单核苷酸多态性（rs35599367 C>T），定义为 CYP3A4*22 等位基因，该等位基因与 CYP3A4 的肝表达和活性降低有关。在本研究中，我们在接受 CsA 为基础的免疫抑制方案的患者队列中研究了这种单核苷酸多态性的临床影响。
共 172 名新诊断的肾移植受者，接受 CsA/霉酚酸酯作为免疫抑制治疗，并参与固定剂量浓度控制研究，对新的 CYP3A4*22 等位基因进行了基因分型。在移植后第 3 天和第 10 天以及第 1、3、6 和 12 个月测量 CsA C（0）和/或 C（2）水平。记录血浆肌酸酐浓度、延迟移植物功能（DGF）和活检证实的急性排斥反应。
在调整已知危险因素后，与 CYP3A41/1 患者相比，CYP3A422 等位基因与 DGF 的发生风险显著相关[比值比（OR）=6.34，95%置信区间（CI（95%）：1.38-29.3），P=0.015]。混合模型分析表明，与 CYP3A41/1 患者相比，CYP3A422 等位基因携带者的总体肌酐清除率低 20%[CI（95%）（-33.1 至-7.2%），P=0.002]。对于 ABCB1 3435C>T，T 变体携带者发生 DGF 的风险低于 CC 患者[CT：OR=0.30，95%CI（0.11-0.77），P=0.011；TT：OR=0.18，95%CI（0.05-0.67），P=0.011]。
CYP3A422 是接受 CsA 为基础免疫抑制治疗的患者发生 DGF 和肌酐清除率降低的危险因素。因此，在移植前对 CYP3A422 等位基因进行基因分型可能有助于临床医生识别接受 CsA 治疗时发生 DGF 和肾功能不良的风险患者。
