Tremmel Roman, Zhou Yitian, Schwab Matthias, Lauschke Volker M
Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany.
University Tübingen, Tübingen, Germany.
NPJ Genom Med. 2023 Sep 8;8(1):24. doi: 10.1038/s41525-023-00371-y.
Genetic variants in drug targets and genes encoding factors involved in drug absorption, distribution, metabolism and excretion (ADME) can have pronounced impacts on drug pharmacokinetics, response, and toxicity. While the landscape of genetic variability at the level of single nucleotide variants (SNVs) has been extensively studied in these pharmacogenetic loci, their structural variation is only poorly understood. Thus, we systematically analyzed the genetic structural variability across 908 pharmacogenes (344 ADME genes and 564 drug targets) based on publicly available whole genome sequencing data from 10,847 unrelated individuals. Overall, we extracted 14,984 distinct structural variants (SVs) ranging in size from 50 bp to 106 Mb. Each individual harbored on average 10.3 and 1.5 SVs with putative functional effects that affected the coding regions of ADME genes and drug targets, respectively. In addition, by cross-referencing pharmacogenomic SVs with experimentally determined binding data of 224 transcription factors across 130 cell types, we identified 1276 non-coding SVs that overlapped with gene regulatory elements. Based on these data, we estimate that non-coding structural variants account for 22% of the genetically encoded pharmacogenomic variability. Combined, these analyses provide the first comprehensive map of structural variability across pharmacogenes, derive estimates for the functional impact of non-coding SVs and incentivize the incorporation of structural genomic data into personalized drug response predictions.
药物靶点以及编码参与药物吸收、分布、代谢和排泄（ADME）相关因子的基因中的遗传变异，可能会对药物的药代动力学、反应及毒性产生显著影响。虽然在这些药物遗传学位点上，单核苷酸变异（SNV）水平的遗传变异性已得到广泛研究，但其结构变异却鲜为人知。因此，我们基于来自10847名无亲缘关系个体的公开全基因组测序数据，系统分析了908个药物基因（344个ADME基因和564个药物靶点）的遗传结构变异性。总体而言，我们提取了14984个不同的结构变异（SV），其大小从50bp到106Mb不等。每个个体平均携带10.3个和1.5个具有推定功能效应的SV，分别影响ADME基因和药物靶点的编码区。此外，通过将药物基因组SV与130种细胞类型中224种转录因子的实验测定结合数据进行交叉参考，我们鉴定出1276个与基因调控元件重叠的非编码SV。基于这些数据，我们估计非编码结构变异占遗传编码的药物基因组变异性的22%。综合来看，这些分析提供了首张药物基因结构变异性的全面图谱，得出了非编码SV功能影响的估计值，并促使将结构基因组数据纳入个性化药物反应预测中。
