Centre for Medicine Use and Safety, Monash University, Parkville, VIC, Australia.
MyDNA Life, Australia Limited, South Yarra, VIC, Australia.
J Neural Transm (Vienna). 2019 Jan;126(1):5-18. doi: 10.1007/s00702-018-1922-0. Epub 2018 Sep 6.
Common polymorphisms in the genes encoding CYP2D6, CYP2C19, CYP2C9 and VKORC1 enzymes have an important role in predicting the occurrence of adverse effects and the efficacy of substrate medications. Drug-induced changes to the enzyme's phenotype, a process called phenoconversion, comprise another important factor contributing to interindividual variability in drug response. To date, there is lack of data on the frequency of these common polymorphisms and phenoconversion in the pan-ethnic Australian population. The aim of this study was to (1) describe allele, genotype and phenotype frequencies for CYP2D6, CYP2C19, CYP2C9 and VKORC1 enzymes in the pan-ethnic Australian population and (2) evaluate the frequency of actionable pharmacogenomic (PGx) variants and phenoconversion. Frequencies were calculated using the records of 5408 Australian patients (obtained from myDNA's propriety database), who were consecutively tested with the DNAdose PGx test which included the CYP2D6, CYP2C19, CYP2C9 and VKORC1 genes. In 2509 patients with listed medications at the time of testing, phenoconversion frequencies were calculated for CYP2D6, CYP2C19 and CYP2C9 enzymes. Allele, genotype and phenotype frequencies in our Australian patients correlated with a Caucasian population. Approximately 96% of patients had at least one actionable PGx variant. A five-fold increase in the frequency of poor metabolisers (PMs) for CYP2D6 and CYP2C19 was predicted by phenoconversion. Our study results indicate a high frequency of actionable PGx variants in our Australian population. With the addition of drug-induced phenoconversion, our results provide further support for the utilisation of PGx testing in clinical practice as another tool assisting prescribers in the application of personalised medicine.
常见的 CYP2D6、CYP2C19、CYP2C9 和 VKORC1 基因多态性在预测不良反应的发生和底物药物的疗效方面具有重要作用。酶表型的药物诱导变化,称为表型转化,是导致药物反应个体间差异的另一个重要因素。迄今为止,关于这些常见多态性和表型转化在泛澳大利亚人群中的频率缺乏数据。本研究的目的是:(1)描述泛澳大利亚人群 CYP2D6、CYP2C19、CYP2C9 和 VKORC1 酶的等位基因、基因型和表型频率;(2)评估可操作的药物基因组学 (PGx) 变异体和表型转化的频率。使用从 myDNA 专有数据库中获得的 5408 名澳大利亚患者的记录,使用 DNAdose PGx 测试计算频率,该测试包括 CYP2D6、CYP2C19、CYP2C9 和 VKORC1 基因。在 2509 名测试时列出药物的患者中,计算 CYP2D6、CYP2C19 和 CYP2C9 酶的表型转化频率。我们澳大利亚患者的等位基因、基因型和表型频率与白种人群相关。大约 96%的患者至少有一种可操作的 PGx 变异体。表型转化预测 CYP2D6 和 CYP2C19 的不良代谢者 (PM) 频率增加五倍。我们的研究结果表明,我们澳大利亚人群中存在高频率的可操作 PGx 变异体。随着药物诱导表型转化的增加,我们的结果进一步支持在临床实践中使用 PGx 测试作为另一种工具,帮助临床医生应用个性化医学。