利用与电子病历相关联的 DNA 生物库来描述肾移植受者他克莫司剂量需求的药物基因组预测因子。
The use of a DNA biobank linked to electronic medical records to characterize pharmacogenomic predictors of tacrolimus dose requirement in kidney transplant recipients.
机构信息
Division of Nephrology, Vanderbilt University Medical Center, Nashville, Tennesse, USA.
出版信息
Pharmacogenet Genomics. 2012 Jan;22(1):32-42. doi: 10.1097/FPC.0b013e32834e1641.
OBJECTIVE
Tacrolimus, an immunosuppressive drug widely prescribed in kidney transplantation, requires therapeutic drug monitoring due to its marked interindividual pharmacokinetic variability and narrow therapeutic index. Previous studies have established that CYP3A5 rs776746 is associated with tacrolimus clearance, blood concentration, and dose requirement. The importance of other drug absorption, distribution, metabolism, and elimination (ADME) gene variants has not been well characterized.
METHODS
We used novel DNA biobank and electronic medical record resources to identify ADME variants associated with tacrolimus dose requirement. Broad ADME genotyping was performed on 446 kidney transplant recipients, who had been dosed to a steady state with tacrolimus. The cohort was obtained from Vanderbilt's DNA biobank, BioVU, which contains linked deidentified electronic medical record data. Genotyping included Affymetrix drug-metabolizing enzymes and transporters Plus (1936 polymorphisms), custom Sequenom Massarray iPLEX Gold assay (95 polymorphisms), and ancestry-informative markers. The primary outcome was tacrolimus dose requirement defined as blood concentration to dose ratio.
RESULTS
In analyses, which adjusted for race and other clinical factors, we replicated the association of tacrolimus blood concentration to dose ratio with CYP3A5 rs776746 (P=7.15×10), and identified associations with nine variants in linkage disequilibrium with rs776746, including eight CYP3A4 variants. No NR1I2 variants were significantly associated. Age, weight, and hemoglobin were also significantly associated with the outcome. In final models, rs776746 explained 39% of variability in dose requirement and 46% was explained by the model containing clinical covariates.
CONCLUSION
This study highlights the utility of DNA biobanks and electronic medical records for tacrolimus pharmacogenomic research.
目的
他克莫司是一种在肾移植中广泛应用的免疫抑制剂药物，由于其个体间药代动力学变异性大且治疗指数较窄，因此需要进行治疗药物监测。先前的研究已经证实 CYP3A5 rs776746 与他克莫司清除率、血药浓度和剂量需求有关。其他药物吸收、分布、代谢和排泄（ADME）基因变异的重要性尚未得到很好的描述。
方法
我们利用新的 DNA 生物库和电子病历资源来确定与他克莫司剂量需求相关的 ADME 变异。对 446 例接受他克莫司稳态剂量治疗的肾移植受者进行了广泛的 ADME 基因分型。该队列来自范德比尔特大学的 DNA 生物库 BioVU，其中包含链接的匿名电子病历数据。基因分型包括 Affymetrix 药物代谢酶和转运体 Plus（1936 个多态性）、定制的 Sequenom Massarray iPLEX Gold assay（95 个多态性）和遗传信息标记。主要结局是他克莫司剂量需求，定义为血药浓度与剂量的比值。
结果
在调整种族和其他临床因素的分析中，我们复制了 CYP3A5 rs776746 与他克莫司血药浓度与剂量比值的关联（P=7.15×10），并确定了与 rs776746 连锁不平衡的 9 个变异的关联，包括 8 个 CYP3A4 变异。NR1I2 变异没有显著关联。年龄、体重和血红蛋白也与结果显著相关。在最终模型中，rs776746 解释了剂量需求变异性的 39%，而包含临床协变量的模型解释了 46%。
结论
本研究强调了 DNA 生物库和电子病历在他克莫司药物基因组学研究中的应用。
Zotero 插件