Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany.
LIFE Research Center for Civilization Diseases, University of Leipzig, Leipzig, Germany.
PLoS One. 2022 Apr 21;17(4):e0266897. doi: 10.1371/journal.pone.0266897. eCollection 2022.
For many drugs, mechanisms of action with regard to desired effects and/or unwanted side effects are only incompletely understood. To investigate possible pleiotropic effects and respective molecular mechanisms, we describe here a catalogue of commonly used drugs and their impact on the blood transcriptome.
From a population-based cohort in Germany (LIFE-Adult), we collected genome-wide gene-expression data in whole blood using in Illumina HT12v4 micro-arrays (n = 3,378; 19,974 gene expression probes per individual). Expression profiles were correlated with the intake of active substances as assessed by participants' medication. This resulted in a catalogue of fourteen substances that were identified as associated with differential gene expression for a total of 534 genes. As an independent replication cohort, an observational study of patients with suspected or confirmed stable coronary artery disease (CAD) or myocardial infarction (LIFE-Heart, n = 3,008, 19,966 gene expression probes per individual) was employed. Notably, we were able to replicate differential gene expression for three active substances affecting 80 genes in peripheral blood mononuclear cells (carvedilol: 25; prednisolone: 17; timolol: 38). Additionally, using gene ontology enrichment analysis, we demonstrated for timolol a significant enrichment in 23 pathways, 19 of them including either GPER1 or PDE4B. In the case of carvedilol, we showed that, beside genes with well-established association with hypertension (GPER1, PDE4B and TNFAIP3), the drug also affects genes that are only indirectly linked to hypertension due to their effects on artery walls or their role in lipid biosynthesis.
Our developed catalogue of blood gene expressions profiles affected by medication can be used to support both, drug repurposing and the identification of possible off-target effects.
对于许多药物，其作用机制（包括预期效果和/或不良副作用）尚不完全清楚。为了研究可能的多效性作用及其相应的分子机制，我们在此描述了一个常用药物目录及其对血液转录组的影响。
我们从德国一项基于人群的队列研究（LIFE-Adult）中，使用 Illumina HT12v4 微阵列收集了全血的全基因组基因表达数据（n=3378；每个个体有 19974 个基因表达探针）。通过参与者的药物摄入情况，将表达谱与活性物质的摄入情况相关联。这产生了一个目录，其中包含 14 种被认为与基因表达差异相关的物质，总共涉及 534 个基因。作为一个独立的复制队列，我们使用疑似或确诊稳定型冠状动脉疾病（CAD）或心肌梗死患者的观察性研究（LIFE-Heart，n=3008；每个个体有 19966 个基因表达探针）进行了验证。值得注意的是，我们能够在 3008 名患者的外周血单核细胞中复制三种活性物质对 80 个基因的差异表达，这些物质分别为卡维地洛（25 个）、泼尼松龙（17 个）和噻吗洛尔（38 个）。此外，我们通过基因本体论富集分析，展示了噻吗洛尔在 23 条途径中显著富集，其中 19 条途径包括 GPER1 或 PDE4B。对于卡维地洛，我们发现，除了与高血压密切相关的基因（GPER1、PDE4B 和 TNFAIP3）外，该药物还会影响与高血压仅有间接关系的基因，这些基因的作用是影响动脉壁或参与脂质生物合成。
我们开发的受药物影响的血液基因表达谱目录可用于支持药物再利用和识别可能的脱靶效应。
