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首页> 外文期刊>Pharmacogenetics and genomics >The use of a DNA biobank linked to electronic medical records to characterize pharmacogenomic predictors of tacrolimus dose requirement in kidney transplant recipients.
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The use of a DNA biobank linked to electronic medical records to characterize pharmacogenomic predictors of tacrolimus dose requirement in kidney transplant recipients.

机译：使用与电子病历关联的DNA生物库来表征肾移植受者中他克莫司剂量需求的药物基因组学预测因子。

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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=7.15x10), 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.
机译：目的：他克莫司是肾脏移植中广泛使用的一种免疫抑制药物，由于其个体间的药代动力学差异和狭窄的治疗指数，需要对其进行治疗药物监测。先前的研究已经确定CYP3A5 rs776746与他克莫司清除率，血药浓度和剂量要求有关。其他药物吸收，分布，代谢和消除（ADME）基因变异的重要性尚未得到很好的描述。方法：我们使用了新颖的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变异体。对446名接受他克莫司稳定治疗的肾移植受者进行了广泛的ADME基因分型。该研究组来自范德比尔特（Vanderbilt）的DNA生物库BioVU，其中包含链接的身份不明的电子病历数据。基因分型包括Affymetrix药物代谢酶和转运蛋白Plus（1936年多态性），定制的Sequenom Massarray iPLEX Gold检测（95种多态性）和祖先信息标记。主要结果是他克莫司剂量需求，定义为血液浓度与剂量之比。结果：在针对种族和其他临床因素进行调整的分析中，我们复制了他克莫司血药浓度与剂量比与CYP3A5 rs776746的关联（P = 7.15x10），并确定了与rs776746连锁不平衡的9个变异体的关联，包括8个CYP3A4变体。没有NR1I2变体显着相关。年龄，体重和血红蛋白也与结果显着相关。在最终模型中，rs776746解释了39％的剂量需求差异，而46％的解释是包含临床协变量的模型。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实用性。

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