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首页> 外文期刊>Pharmacogenetics and genomics >The new CYP3A4 intron 6 C>T polymorphism (CYP3A4*22) is associated with an increased risk of delayed graft function and worse renal function in cyclosporine-treated kidney transplant patients
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The new CYP3A4 intron 6 C>T polymorphism (CYP3A4*22) is associated with an increased risk of delayed graft function and worse renal function in cyclosporine-treated kidney transplant patients

机译：新的CYP3A4内含子6 C> T多态性（CYP3A4 * 22）与环孢素治疗的肾移植患者中延迟移植功能和肾功能恶化的风险增加相关

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OBJECTIVE: 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. MATERIALS AND METHODS: 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 C0 and/or C2 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. RESULTS: The CYP3A4*22 allele was significantly associated with a higher risk of DGF compared with the CYP3A4*1/*1 patients after adjustment for known risk factors [odds ratio (OR)=6.34, confidence interval (CI95%: 1.38-29.3), P=0.015]. Mixed-model analysis demonstrated that the overall creatinine clearance was 20% lower in CYP3A4*22 allele carriers compared with CYP3A4*1/*1 patients [CI95% (-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, CI95% (0.11-0.77), P=0.011; TT: OR=0.18, CI95% (0.05-0.67), P=0.011]. CONCLUSION: CYP3A4*22 constitutes a risk factor for DGF and worse creatinine clearance in patients receiving CsA-based immunosuppressive therapy. Therefore, pretransplant genotyping for the CYP3A4*22 allele might help clinicians to identify patients at risk of DGF and poor renal function when treated with CsA.
机译：目的：环孢菌素A（CsA）是细胞色素P450 3A4（CYP3A4）的底物。最近，在CYP3A4中新发现的内含子6单核苷酸多态性（rs35599367 C> T）定义了CYP3A4 * 22等位基因，已与肝脏中CYP3A4的表达和活性降低有关。在本研究中，在接受基于CsA的免疫抑制方案的一组患者中研究了这种单核苷酸多态性的临床影响。材料与方法：共筛选了172名接受CsA /霉酚酸酯作为免疫抑制治疗并参加了固定剂量浓度对照研究的新生肾脏移植受者，以进行新的CYP3A4 * 22等位基因的基因分型。在移植后第3天和第10天以及第1、3、6和12个月测量CsA C0和/或C2水平。记录血浆肌酐浓度，延迟移植功能（DGF）和活检证实的急性排斥反应。结果：校正已知危险因素后，CYP3A4 * 22等位基因与CYP3A4 * 1 / * 1患者的DGF风险显着相关[比值比（OR）= 6.34，置信区间（CI95％：1.38-29.3） ），P = 0.015]。混合模型分析表明，与CYP3A4 * 1 / * 1患者相比，CYP3A4 * 22等位基因携带者的总体肌酐清除率降低20％[CI95％（-33.1至-7.2％），P = 0.002]。对于ABCB1 3435C> T，与CC患者相比，T变异携带者发生DGF的风险降低[CT：OR = 0.30，CI95％（0.11-0.77），P = 0.011; TT：OR ＝ 0.18，CI95％（0.05-0.67），P ＝ 0.011]。结论：CYP3A4 * 22是接受基于CsA的免疫抑制治疗的患者DGF和肌酐清除率降低的危险因素。因此，CYP3A4 * 22等位基因的移植前基因分型可能有助于临床医生确定接受CsA治疗时有DGF风险和肾功能不良的患者。

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