Samsung Advanced Institute for Health Sciences & Technology (SAIHST), Sungkyunkwan University, Samsung Medical Center, Seoul, Republic of Korea.
Medical and Population Genetics and Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA; Department of Medicine, Harvard Medical School, Boston, MA, USA.
Cell Rep Med. 2023 Sep 19;4(9):101112. doi: 10.1016/j.xcrm.2023.101112. Epub 2023 Aug 14.
Drug targets with genetic support are several-fold more likely to succeed in clinical trials. We introduce a genetic-driven approach based on causal inferences that can inform drug target prioritization, repurposing, and adverse effects of using lipid-lowering agents. Given that a multi-trait approach increases the power to detect meaningful variants/genes, we conduct multi-omics and multi-trait analyses, followed by network connectivity investigations, and prioritize 30 potential therapeutic targets for dyslipidemia, including SORT1, PSRC1, CELSR2, PCSK9, HMGCR, APOB, GRN, HFE2, FJX1, C1QTNF1, and SLC5A8. 20% (6/30) of prioritized targets from our hypothesis-free drug target search are either approved or under investigation for dyslipidemia. The prioritized targets are 22-fold higher in likelihood of being approved or under investigation in clinical trials than genome-wide association study (GWAS)-curated targets. Our results demonstrate that the genetic-driven approach used in this study is a promising strategy for prioritizing targets while informing about the potential adverse effects and repurposing opportunities.
具有遗传支持的药物靶点在临床试验中成功的可能性要高出数倍。我们引入了一种基于因果推理的遗传驱动方法，该方法可以为药物靶点的优先级排序、重新定位和降脂药物的不良反应提供信息。鉴于多特征方法可以提高检测有意义的变异/基因的能力，我们进行了多组学和多特征分析，然后进行网络连接性研究，为血脂异常优先排序了 30 个潜在的治疗靶点，包括 SORT1、PSRC1、CELSR2、PCSK9、HMGCR、APOB、GRN、HFE2、FJX1、C1QTNF1 和 SLC5A8。在我们无假设的药物靶点搜索中，优先排序的靶点有 6/30%（6/30）已经被批准或正在研究用于血脂异常。与全基因组关联研究（GWAS） curated 靶点相比，优先排序的靶点在临床试验中被批准或正在研究的可能性要高出 22 倍。我们的研究结果表明，本研究中使用的遗传驱动方法是一种有前途的策略，可用于优先排序靶点，同时提供潜在的不良反应和重新定位机会的信息。
