Department of Physiology and Pharmacology, Section of Pharmacogenetics, Karolinska Institutet, Stockholm, Sweden.
J Med Genet. 2018 Sep;55(9):617-627. doi: 10.1136/jmedgenet-2018-105429. Epub 2018 Jul 3.
Adverse drug reactions are a major concern in drug development and clinical therapy. Genetic polymorphisms in genes involved in drug metabolism and transport are major determinants of treatment efficacy and adverse reactions, and constitute important biomarkers for drug dosing, efficacy and safety. Importantly, human populations and subgroups differ substantially in their pharmacogenetic variability profiles, with important consequences for personalised medicine strategies and precision public health approaches. Despite their long migration history, Ashkenazi Jews constitute a rather isolated population with a unique genetic signature that is distinctly different from other populations.
To provide a comprehensive overview of the pharmacogenetic profile in Ashkenazim.
We analysed next-generation sequencing data from 5076 Ashkenazim individuals and used sequence data from 117 425 non-Jewish individuals as reference.
We derived frequencies of 164 alleles in 17 clinically relevant pharmacogenes and derived profiles of putative functional consequences, providing the most comprehensive data set of Jewish pharmacogenetic diversity published to date. Furthermore, we detected 127 variants with an aggregated frequency of 20.7% that were specifically found in Ashkenazim, of which 55 variants were putatively deleterious (aggregated frequency of 9.4%).
The revealed pattern of pharmacogenetic variability in Ashkenazi Jews is distinctly different from other populations and is expected to translate into unique functional consequences, especially for the metabolism of CYP2A6, CYP2C9, NAT2 and VKORC1 substrates. We anticipate that the presented data will serve as a powerful resource for the guidance of pharmacogenetic treatment decisions and the optimisation of population-specific genotyping strategies in the Ashkenazi diaspora.
药物不良反应是药物开发和临床治疗中的一个主要关注点。参与药物代谢和转运的基因中的遗传多态性是治疗效果和不良反应的主要决定因素，也是药物剂量、疗效和安全性的重要生物标志物。重要的是，人类群体和亚群在其药物遗传学变异性特征方面存在很大差异，这对个体化医学策略和精准公共卫生方法有重要影响。尽管阿什肯纳齐犹太人有着悠久的迁徙历史，但他们构成了一个相当孤立的群体，具有独特的遗传特征，与其他群体明显不同。
提供阿什肯纳齐人的药物遗传学概况综述。
我们分析了 5076 名阿什肯纳齐人的下一代测序数据，并将 117425 名非犹太人个体的序列数据作为参考。
我们得出了 17 个临床相关药物基因中 164 个等位基因的频率，并得出了假定功能后果的图谱，提供了迄今为止发表的最全面的犹太药物遗传学多样性数据集。此外，我们检测到 127 个频率为 20.7%的特定于阿什肯纳齐人的变体，其中 55 个变体被认为是有害的（频率为 9.4%）。
阿什肯纳齐犹太人中药物遗传学变异性的表现模式与其他群体明显不同，预计会产生独特的功能后果，特别是对 CYP2A6、CYP2C9、NAT2 和 VKORC1 底物的代谢。我们预计，所提供的数据将成为指导药物遗传学治疗决策和优化阿什肯纳齐散居地特定人群基因分型策略的有力资源。
