Identifying therapeutic drug targets using bidirectional effect genes.
Identifying therapeutic drug targets using bidirectional effect genes.
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DOI：
10.1038/s41467-021-21843-8
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发表时间：
2021-04-13
影响因子：
16.6
通讯作者：
Cardon LR
中科院分区：
文献类型：
--
作者：
Estrada K;Froelich S;Wuster A;Bauer CR;Sterling T;Clark WT;Ru Y;Trinidad M;Nguyen HP;Luu AR;Wendt DJ;Yogalingam G;Yu GK;LeBowitz JH;Cardon LR
将基因优先翻译为常见疾病的治疗药物一直具有挑战性。在这里，我们提出了一种方法，以确定药物靶点的成功概率高，重点是基因的功能获得（GoF）和功能丧失（LoF）突变与表型的相反影响（双向效应选择的目标，最佳）。我们发现了98个最好的基因用于各种适应症。靶向这些基因的药物获得批准的可能性是非BEST基因的3.8倍。我们专注于五个基因（IGF1R，NPPC，NPR 2，FGFR 3和SHOX）与身高的双向影响的证据。这些基因中罕见的蛋白质改变变体导致特发性身材矮小（ISS）的风险显著增加（OR = 2.75，p = 3.99 × 10−8）。最后，使用功能性实验，我们证明，添加外源性CNP类似物（编码的NPPC）拯救的表型，从而验证其作为ISS的治疗性治疗的潜力。我们的结果显示了寻找双向效应以识别和验证药物靶点的价值。优先考虑基因作为潜在的药物靶点是具有挑战性的，并且一旦在人体中测试疗效就往往不成功。在这里，作者提出了一种鉴定药物靶点的方法，该方法使用与表型双向效应相关的功能获得或丧失突变的证据。
Prioritizing genes for translation to therapeutics for common diseases has been challenging. Here, we propose an approach to identify drug targets with high probability of success by focusing on genes with both gain of function (GoF) and loss of function (LoF) mutations associated with opposing effects on phenotype (Bidirectional Effect Selected Targets, BEST). We find 98 BEST genes for a variety of indications. Drugs targeting those genes are 3.8-fold more likely to be approved than non-BEST genes. We focus on five genes (IGF1R, NPPC, NPR2, FGFR3, and SHOX) with evidence for bidirectional effects on stature. Rare protein-altering variants in those genes result in significantly increased risk for idiopathic short stature (ISS) (OR = 2.75, p = 3.99 × 10−8). Finally, using functional experiments, we demonstrate that adding an exogenous CNP analog (encoded by NPPC) rescues the phenotype, thus validating its potential as a therapeutic treatment for ISS. Our results show the value of looking for bidirectional effects to identify and validate drug targets. Prioritising genes as potential drug targets is challenging and often unsuccessful once testing efficacy in humans. Here, the authors propose an approach to identifying drug targets that uses evidence from gain- or loss-of-function mutations associated with bidirectional effects on phenotypes.
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影响因子：
5.8
作者：
Hanley, Patrick C.;Kanwar, Harsh S.;Levine, Michael A.
通讯作者：
Levine, Michael A.
影响因子：
64.5
作者：
Boyle EA;Li YI;Pritchard JK
通讯作者：
Pritchard JK
DOI：
10.1038/gim.2017.159
发表时间：
2018-06
期刊：
Genetics in medicine : official journal of the American College of Medical Genetics
影响因子：
--
作者：
Hauer NN;Popp B;Schoeller E;Schuhmann S;Heath KE;Hisado-Oliva A;Klinger P;Kraus C;Trautmann U;Zenker M;Zweier C;Wiesener A;Abou Jamra R;Kunstmann E;Wieczorek D;Uebe S;Ferrazzi F;Büttner C;Ekici AB;Rauch A;Sticht H;Dörr HG;Reis A;Thiel CT
通讯作者：
Thiel CT
影响因子：
64.8
作者：
Karczewski, Konrad J;Francioli, Laurent C;MacArthur, Daniel G
通讯作者：
MacArthur, Daniel G
影响因子：
30.8
作者：
Jonathan, C;Pertsemlidis, A;Hobbs, HH
通讯作者：
Hobbs, HH