Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN, USA.
Pharmacogenomics J. 2020 Oct;20(5):736-745. doi: 10.1038/s41397-020-0163-4. Epub 2020 Feb 14.
Leukopenia is a serious, frequent side effect associated with azathioprine use. Currently, we use thiopurine methyltransferase (TPMT) testing to predict leukopenia in patients taking azathioprine. We hypothesized that a risk score incorporating additional clinical and genetic variables would improve the prediction of azathioprine-associated leukopenia. In the discovery phase, we developed four risk score models: (1) age, sex, and TPMT metabolizer status; (2) model 1 plus additional clinical variables; (3) sixty candidate single nucleotide polymorphisms; and (4) model 2 plus model 3. The area under the receiver-operating-characteristic curve (AUC) of the risk scores was 0.59 (95% CI: 0.54-0.64), 0.75 (0.71-0.80), 0.66 (0.61-0.71), and 0.78 (0.74-0.82) for models 1, 2, 3, and 4, respectively. During the replication phase, models 2 and 4 (AUC = 0.64, 95% CI: 0.59-0.70 and AUC = 0.63, 95% CI: 0.58-0.69, respectively) were significant in an independent group. Compared with TPMT testing alone, additional genetic and clinical variables improve the prediction of azathioprine-associated leukopenia.
白细胞减少症是一种与硫唑嘌呤使用相关的严重且常见的副作用。目前，我们使用巯嘌呤甲基转移酶（TPMT）检测来预测服用硫唑嘌呤的患者的白细胞减少症。我们假设，纳入其他临床和遗传变量的风险评分将提高预测硫唑嘌呤相关白细胞减少症的能力。在发现阶段，我们开发了四个风险评分模型：（1）年龄、性别和 TPMT 代谢状态；（2）模型 1 加其他临床变量；（3）六十个候选单核苷酸多态性；和（4）模型 2 加模型 3。风险评分的受试者工作特征曲线（ROC）下面积（AUC）分别为 0.59（95%CI：0.54-0.64）、0.75（0.71-0.80）、0.66（0.61-0.71）和 0.78（0.74-0.82），分别对应模型 1、2、3 和 4。在复制阶段，模型 2 和 4（AUC=0.64，95%CI：0.59-0.70 和 AUC=0.63，95%CI：0.58-0.69）在独立组中具有统计学意义。与 TPMT 检测相比，额外的遗传和临床变量可改善硫唑嘌呤相关白细胞减少症的预测。
