Identification and functional validation of novel pharmacogenomic variants using a next-generation sequencing-based approach for clinical pharmacogenomics
Identification and functional validation of novel pharmacogenomic variants using a next-generation sequencing-based approach for clinical pharmacogenomics
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DOI：
10.1016/j.phrs.2022.106087
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发表时间：
2022-01-17
影响因子：
9.3
通讯作者：
Patrinos, George P.
中科院分区：
文献类型：
--
作者：
Siamoglou, Stavroula;Koromina, Maria;Patrinos, George P.
药代动力学和药物反应的个体间变异很大程度上受到对药物处置很重要的基因中的单核苷酸变异 (SNV) 和拷贝数变异 (CNV) 的影响。如今，大量研究采用下一代测序来捕获影响药物反应的罕见和新颖的药物基因组 (PGx) 变异。为了解决这些问题，我们提出了全面的端到端分析工作流程，从靶向 PGx panel 重新测序到计算机分析流程和体外验证测定。具体来说，我们表明，预测或推定预测为功能有害的新型药物遗传学错义变体会显着改变 CYP2D6 和 CYP2C19 蛋白的蛋白活性水平。我们进一步证明，通过功能性体外验证测定定制的变体优先级流程为新型 PGx 变体的有害影响提供了支持证据。所提出的工作流程可以为将 PGx 测试的下一代测序整合到常规临床实践中提供基础。
Inter-individual variability in pharmacokinetics and drug response is heavily influenced by single-nucleotide variants (SNVs) and copy-number variations (CNVs) in genes with importance for drug disposition. Nowadays, a plethora of studies implement next generation sequencing to capture rare and novel pharmacogenomic (PGx) variants that influence drug response. To address these issues, we present a comprehensive end-to-end analysis workflow, beginning from targeted PGx panel re-sequencing to in silico analysis pipelines and in vitro validation assays. Specifically, we show that novel pharmacogenetic missense variants that are predicted or putatively predicted to be functionally deleterious, significantly alter protein activity levels of CYP2D6 and CYP2C19 proteins. We further demonstrate that variant priorization pipelines tailored with functional in vitro validation assays provide supporting evidence for the deleterious effect of novel PGx variants. The proposed workflow could provide the basis for integrating next-generation sequencing for PGx testing into routine clinical practice.