I 型和 II 型肌苷单磷酸脱氢酶基因的多态性与吗替麦考酚酯治疗患者的临床结局的关系。
Polymorphisms in type I and II inosine monophosphate dehydrogenase genes and association with clinical outcome in patients on mycophenolate mofetil.
机构信息
INSERM, UMR-S850, Limoges, France.
出版信息
Pharmacogenet Genomics. 2010 Sep;20(9):537-43. doi: 10.1097/FPC.0b013e32833d8cf5.
BACKGROUND
Type I and II inosine monophosphate dehydrogenases (IMPDH) are the targets of mycophenolic acid (MPA), a widely used immunosuppressant. The aims of this study were: to check the presence of controversial polymorphisms in the IMPDH II gene; to look for new ones; and to investigate potential associations between the most frequent SNPs in both IMPDH genes and clinical outcome in renal transplant recipients.
METHODS
The DNA and clinical data of 456 patients from two clinical trials were collected. We sequenced the IMPDH II gene in 80 patients and we genotyped the 456 patients' DNA for the IMPDH II rs4974081, rs11706052, 787C>T and the IMPDH I rs2278293 and rs2278294 SNPs, all of which were earlier reported to be potentially involved in MPA treatment related outcome. We investigated the associations of biopsy proven acute rejection (BPAR), leucopenia, cytomegalovirus infections and other infections with these IMPDH polymorphisms, as well as with demographic, biological and treatment data using multivariate analysis.
RESULTS
Many IMPDH II variant alleles referenced in Genbank were not detected and no new polymorphisms were identified. In the whole group of 456 patients, the IMPDH I rs2278294 SNP was associated with a lower risk of BPAR and a higher risk of leucopenia over the first year post-transplantation. No other IMPDH I or IMPDH II polymorphism was significantly associated with any clinical outcome. Interestingly, calcineurin inhibitor and MPA exposures below the therapeutic range increased the risk of BPAR. Cytomegalovirus infection was the factor most closely linked with leucopenia, whereas tacrolimus was associated with fewer infections than cyclosporine.
CONCLUSION
IMPDH II genotyping may not improve MPA treatment outcome over the first year post-transplantation, in contrast to MPA and calcineurine inhibitor therapeutic drug monitoring and IMPDH I genotyping.
背景
I 型和 II 型肌苷单磷酸脱氢酶（IMPDH）是霉酚酸（MPA）的靶标，MPA 是一种广泛使用的免疫抑制剂。本研究的目的是：检查 IMPDH II 基因中是否存在有争议的多态性；寻找新的多态性；并研究两种 IMPDH 基因中最常见的 SNP 与肾移植受者临床结局之间的潜在关联。
方法
收集了来自两项临床试验的 456 名患者的 DNA 和临床数据。我们对 80 名患者的 IMPDH II 基因进行了测序，并对 456 名患者的 DNA 进行了 IMPDH II rs4974081、rs11706052、787C>T 和 IMPDH I rs2278293 和 rs2278294SNP 的基因分型，这些 SNP 之前都被报道可能与 MPA 治疗相关的结果有关。我们使用多变量分析调查了这些 IMPDH 多态性与活检证实的急性排斥反应（BPAR）、白细胞减少症、巨细胞病毒感染和其他感染以及与人口统计学、生物学和治疗数据的关联。
结果
在 Genbank 中引用的许多 IMPDH II 变体等位基因未被检测到，也未发现新的多态性。在 456 名患者的整个群体中，IMPDH I rs2278294 SNP 与移植后第一年 BPAR 的风险降低和白细胞减少症的风险升高相关。其他 IMPDH I 或 IMPDH II 多态性与任何临床结局均无显著相关性。有趣的是，钙调神经磷酸酶抑制剂和 MPA 暴露低于治疗范围会增加 BPAR 的风险。巨细胞病毒感染与白细胞减少症最密切相关，而与环孢素相比，他克莫司与更少的感染相关。
结论
与 MPA 和钙调神经磷酸酶抑制剂治疗药物监测和 IMPDH I 基因分型相比，移植后第一年 IMPDH II 基因分型可能不会改善 MPA 治疗结果。
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