A model of prediction system for adverse cardiovascular reactions by calcineurin inhibitors among patients with renal transplants using gene-based single-nucleotide polymorphisms
A model of prediction system for adverse cardiovascular reactions by calcineurin inhibitors among patients with renal transplants using gene-based single-nucleotide polymorphisms
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DOI：
10.1007/s10038-005-0275-3
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发表时间：
2005-09-01
影响因子：
3.5
通讯作者：
Ohnishi, Y
中科院分区：
文献类型：
--
作者：
Mushiroda, T;Saito, S;Ohnishi, Y
药物基因组学信息在诊断检测中的应用有望改善药物疗效和毒性的预测，从而为个体患者提供适当的治疗方案。心血管事件是接受钙调磷酸酶抑制剂（CNI）治疗的移植患者中常见的严重药物不良反应（ADR）。我们使用50，947个基于基因的单核苷酸多态性（SNPs）进行了病例对照关联研究，以确定72名接受CNI治疗的肾移植受者中可能与心血管危险因素相关的遗传变异。在接受环孢菌素或他克莫司治疗的患者中，心血管事件的总体发生率为13.9%（10/72）; 6例患者出现心律失常（8.3%），2例患者出现缺血性心脏病（2.8%），2例患者出现心力衰竭（2.8%）。在全基因组关联研究结果的基础上，我们试图建立一个评分系统来预测环孢素和他克莫司心血管毒性的个体风险。预测性能的估计进行了内部留一交叉验证测试。当我们将心律失常、缺血性心脏病和心力衰竭病例作为具有心脏毒性表型的受试者时，使用前八个SNP将10名ADR患者中的9名和62名非ADR患者中的50名正确地分类到相应的类别中。此外，对照人群（n = 246）中评分超过临界值的个体比例（11.0%）接近既往临床研究中肾移植患者的心血管ADR频率（8.3%）。我们的研究结果表明，预测CNI诱导的心血管并发症可以改善肾移植患者的预后和生活质量，并改善免疫抑制方案。
The application of pharmacogenomic information to diagnostic assays is expected to improve the prediction of drug efficacy and toxicity, leading to appropriate therapeutic regimens for individual patients. Cardiovascular events are common and severe adverse drug reactions (ADRs) among transplant patients treated with calcineurin inhibitors (CNIs). We conducted case-control association studies using 50,947 gene-based single-nucleotide polymorphisms (SNPs) to identify genetic variations that might be associated with cardiovascular risk factors in 72 renal transplant recipients with CNI therapy. The overall incidence of cardiovascular events was 13.9% (10/72) among patients receiving cyclosporine or tacrolimus; arrhythmias in six patients (8.3%), ischemic heart diseases in two patients (2.8%), and heart failure in two patients (2.8%). On the basis of results of the genome-wide association studies, we attempted to establish a scoring system to predict individual risks for cardiovascular toxicity of cyclosporine and tacrolimus. Estimation of the predictive performance was carried out by the use of internal leave-one-out cross-validation test. When we combined arrhythmia, ischemic heart disease and heart failure cases as subjects with a cardiotoxicity phenotype, nine of ten ADR patients and 50 of 62 non-ADR patients were correctly classified into the respective categories using the top eight SNPs. In addition, the proportion of individuals in the control population (n=246) with scores over the cut-off (11.0%) was close to the cardiovascular ADR frequency (8.3%) among renal transplant patients in the previous clinical study. Our results open the possibility that prediction of CNI-induced cardiovascular complications can lead to better prognosis and quality of life among kidney-transplant patients, and to improved immunosuppressive regimens.