Department of Physiology and Pharmacology, Section of Pharmacogenetics, Karolinska Institutet, SE-171 77, Stockholm, Sweden.
Hum Genomics. 2018 May 25;12(1):26. doi: 10.1186/s40246-018-0157-3.
Variability in genes implicated in drug pharmacokinetics or drug response can modulate treatment efficacy or predispose to adverse drug reactions. Besides common genetic polymorphisms, recent sequencing projects revealed a plethora of rare genetic variants in genes encoding proteins involved in drug metabolism, transport, and response.
To understand the global importance of rare pharmacogenetic gene variants, we mapped the variability in 208 pharmacogenes by analyzing exome sequencing data from 60,706 unrelated individuals and estimated the importance of rare and common genetic variants using a computational prediction framework optimized for pharmacogenetic assessments. Our analyses reveal that rare pharmacogenetic variants were strongly enriched in mutations predicted to cause functional alterations. For more than half of the pharmacogenes, rare variants account for the entire genetic variability. Each individual harbored on average a total of 40.6 putatively functional variants, rare variants accounting for 10.8% of these. Overall, the contribution of rare variants was found to be highly gene- and drug-specific. Using warfarin, simvastatin, voriconazole, olanzapine, and irinotecan as examples, we conclude that rare genetic variants likely account for a substantial part of the unexplained inter-individual differences in drug metabolism phenotypes.
Combined, our data reveal high gene and drug specificity in the contributions of rare variants. We provide a proof-of-concept on how this information can be utilized to pinpoint genes for which sequencing-based genotyping can add important information to predict drug response, which provides useful information for the design of clinical trials in drug development and the personalization of pharmacological treatment.
参与药物药代动力学或药物反应的基因中的变异可调节治疗效果或易导致药物不良反应。除常见的遗传多态性外，最近的测序项目揭示了编码参与药物代谢、转运和反应的蛋白的基因中存在大量罕见遗传变异。
为了了解罕见药物遗传学基因变异的全球重要性，我们通过分析 60706 名无关个体的外显子组测序数据来绘制 208 个药物基因的变异图谱，并使用针对药物遗传学评估进行了优化的计算预测框架来估计罕见和常见遗传变异的重要性。我们的分析表明，罕见药物遗传学变异在预测引起功能改变的突变中强烈富集。对于一半以上的药物基因，罕见变异可解释全部遗传变异。每个人平均总共携带 40.6 个推测具有功能的变异，其中罕见变异占 10.8%。总体而言，发现罕见变异的贡献具有高度的基因和药物特异性。以华法林、辛伐他汀、伏立康唑、奥氮平、伊立替康为例，我们得出结论，罕见遗传变异可能是药物代谢表型个体间差异中未被解释的部分的主要原因。
综合来看，我们的数据揭示了罕见变异在基因和药物方面的特异性。我们提供了一个概念验证，说明了如何利用这些信息来确定哪些基因需要进行测序为基础的基因分型，以提供有关药物反应预测的重要信息，这为药物开发临床试验的设计和药理学治疗的个体化提供了有用的信息。
