Amgen, Inc., 360 Binney St., Cambridge, MA, 02142, USA.
Alnylam Pharmaceuticals, Inc., 300 Third St., Cambridge, MA, 02142, USA.
Nat Commun. 2019 Apr 5;10(1):1579. doi: 10.1038/s41467-019-09407-3.
Only a small fraction of early drug programs progress to the market, due to safety and efficacy failures, despite extensive efforts to predict safety. Characterizing the effect of natural variation in the genes encoding drug targets should present a powerful approach to predict side effects arising from drugging particular proteins. In this retrospective analysis, we report a correlation between the organ systems affected by genetic variation in drug targets and the organ systems in which side effects are observed. Across 1819 drugs and 21 phenotype categories analyzed, drug side effects are more likely to occur in organ systems where there is genetic evidence of a link between the drug target and a phenotype involving that organ system, compared to when there is no such genetic evidence (30.0 vs 19.2%; OR = 1.80). This result suggests that human genetic data should be used to predict safety issues associated with drug targets.
尽管在预测安全性方面付出了大量努力，但由于安全性和疗效失败，只有一小部分早期药物项目能够进入市场。描述药物靶点基因自然变异的影响应该是预测特定蛋白质药物治疗引起的副作用的一种有力方法。在这项回顾性分析中，我们报告了药物靶点遗传变异影响的器官系统与观察到的副作用器官系统之间的相关性。在分析的 1819 种药物和 21 种表型类别中，与没有这种遗传证据相比（30.0%对 19.2%；OR=1.80），药物副作用更有可能发生在药物靶点与涉及该器官系统的表型之间存在遗传联系的器官系统中。这一结果表明，应该利用人类遗传数据来预测与药物靶点相关的安全问题。
