Identifying therapeutic targets for rheumatoid arthritis by genomics-driven integrative approaches

Jie Zhang, Xinyu Fang, Jingwei Wu, Zixing Zhang, Min Mu, Dongqing Ye
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Abstract

Genomics-driven drug discovery holds significant promise in identifying and developing novel therapeutic targets. Here, we utilized large-scale genomic data including genome-wide association studies (GWAS), rare variant burden tests in exome sequencing studies (Exome), and protein quantitative trait loci (pQTL), to prioritize therapeutic targets or repurpose drugs in rheumatoid arthritis (RA). We found that prioritized genes covering two approved RA treatment targets (IL6R and CD86), along with several targets currently undergoing active clinical trials for RA. Fifteen proteins were identified as having causalities with RA risk, and three out of them showed strong support for colocalization. BRD2 was nominated as one of the most promising candidates for clinical translation as its wide expression in joint synovial tissues and validation in observational analyses associating with RA incidence. Collectively, our systematic prioritization of drug targets from different genetically informed approaches, and provided a comprehensive insight into therapeutic strategies for RA.
通过基因组学驱动的综合方法确定类风湿关节炎的治疗目标
基因组学驱动的药物发现在确定和开发新型治疗靶点方面大有可为。在这里,我们利用大规模基因组数据,包括全基因组关联研究(GWAS)、外显子组测序研究(Exome)中的罕见变异负荷测试和蛋白质定量性状位点(pQTL),来确定类风湿关节炎(RA)治疗靶点的优先顺序或药物的再利用。我们发现,被优先考虑的基因涵盖了两个已获批准的类风湿关节炎治疗靶点(IL6R 和 CD86),以及几个目前正在积极进行类风湿关节炎临床试验的靶点。有 15 个蛋白质被确定为与 RA 风险有因果关系,其中有 3 个蛋白质显示出强烈的共定位支持。BRD2在关节滑膜组织中广泛表达,并在与RA发病率相关的观察分析中得到验证,因此被提名为最有希望进行临床转化的候选蛋白之一。总之,我们从不同的基因信息方法中对药物靶点进行了系统的优先排序,并对 RA 的治疗策略提供了全面的见解。
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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