编码与非编码人类药物基因组的结构变异。

IF 4.7 2区 医学 Q1 GENETICS & HEREDITY NPJ Genomic Medicine Pub Date : 2023-09-08 DOI:10.1038/s41525-023-00371-y
Roman Tremmel, Yitian Zhou, Matthias Schwab, Volker M Lauschke
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引用次数: 1

摘要

药物靶点和编码药物吸收、分布、代谢和排泄(ADME)因子的基因的遗传变异可对药物的药代动力学、反应和毒性产生显著影响。虽然这些药物遗传位点在单核苷酸变异(snv)水平上的遗传变异性已经得到了广泛的研究,但对它们的结构变异却知之甚少。因此,我们系统地分析了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,这些基因基于公开的10,847个无关联个体的全基因组测序数据。总的来说,我们提取了14984个不同的结构变异(SVs),大小从50 bp到106 Mb不等。每个个体平均携带10.3和1.5个SVs,这些SVs可能分别影响ADME基因和药物靶点的编码区。此外,通过交叉参考药物基因组学sv与实验确定的130种细胞类型中224个转录因子的结合数据,我们确定了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药物基因组变异性的22%。综上所述,这些分析提供了首个药物基因结构变异性的综合图谱,对非编码sv的功能影响进行了估计,并鼓励将结构基因组数据纳入个性化药物反应预测。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

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Structural variation of the coding and non-coding human pharmacogenome.

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.

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来源期刊
NPJ Genomic Medicine
NPJ Genomic Medicine Biochemistry, Genetics and Molecular Biology-Molecular Biology
CiteScore
9.40
自引率
1.90%
发文量
67
审稿时长
17 weeks
期刊介绍: npj Genomic Medicine is an international, peer-reviewed journal dedicated to publishing the most important scientific advances in all aspects of genomics and its application in the practice of medicine. The journal defines genomic medicine as "diagnosis, prognosis, prevention and/or treatment of disease and disorders of the mind and body, using approaches informed or enabled by knowledge of the genome and the molecules it encodes." Relevant and high-impact papers that encompass studies of individuals, families, or populations are considered for publication. An emphasis will include coupling detailed phenotype and genome sequencing information, both enabled by new technologies and informatics, to delineate the underlying aetiology of disease. Clinical recommendations and/or guidelines of how that data should be used in the clinical management of those patients in the study, and others, are also encouraged.
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