利用遗传数据来研究治疗酒精使用障碍和肝毒性的分子靶点和药物再利用候选物。

Leveraging genetic data to investigate molecular targets and drug repurposing candidates for treating alcohol use disorder and hepatotoxicity.

机构信息

Department of Medical and Clinical Psychology, Uniformed Services University, 4301 Jones Bridge Rd, Bethesda, MD, 20814, United States.

出版信息

Drug Alcohol Depend. 2020 Sep 1;214:108155. doi: 10.1016/j.drugalcdep.2020.108155. Epub 2020 Jul 2.

DOI:10.1016/j.drugalcdep.2020.108155

PMID:32652377

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7423741/

Abstract

BACKGROUND

Novel treatments for alcohol use disorder (AUD) and alcohol-related liver disease (ALD) are greatly needed. Genetic information can improve drug discovery rates by facilitating the identification of novel biological targets and potential drugs for repurposing.

METHODS

The present study utilized a recently developed Bayesian approach, Integrative Risk Gene Selector (iRIGS), to identify additional risk genes for alcohol consumption using SNPs from the largest alcohol consumption GWAS to date (N = 941,280). iRIGS incorporates several genomic features and closeness of these genes in network space to compute a posterior probability for protein coding genes near each SNP. We subsequently used the Target Central Resource Database to search for drug-protein interactions for these newly identified genes and previously identified risk genes for alcohol consumption.

RESULTS

We identified several genes that are novel contributions to the previously published alcohol consumption GWAS. Namely, ACVR2A, which is critical for liver function and linked to anxiety and cocaine self-administration, and PRKCE, which has been linked to alcohol self-administration. Notably, only a minority of the SNPs (18.4 %) were linked to genes with confidence (>0.75), underscoring the need to apply multiple methods to assign function to loci. Finally, some previously identified risk genes for alcohol consumption code for proteins that are implicated in liver function and are targeted by drugs, some of which are candidates for managing hepatotoxicity.

CONCLUSIONS

This study demonstrates the value of incorporating regulatory information and drug-protein interaction data to highlight additional molecular targets and drug repurposing candidates for treating AUD and ALD.

摘要

背景

目前非常需要针对酒精使用障碍（AUD）和酒精相关肝病（ALD）的新治疗方法。遗传信息可以通过促进新型生物靶标的鉴定和潜在药物的再利用，提高药物发现率。

方法

本研究利用最近开发的贝叶斯方法，即综合风险基因选择器（iRIGS），利用迄今为止最大的酒精摄入量 GWAS 的 SNP 来识别更多的酒精摄入风险基因（N=941,280）。iRIGS 整合了几种基因组特征，并将这些基因在网络空间中的接近程度纳入计算每个 SNP 附近蛋白质编码基因的后验概率。随后，我们使用靶中央资源数据库搜索这些新鉴定的基因和先前鉴定的酒精摄入风险基因的药物-蛋白相互作用。

结果

我们鉴定了几个基因，它们是先前发表的酒精摄入量 GWAS 的新贡献。即 ACVR2A，它对肝功能至关重要，与焦虑和可卡因自我给药有关，以及 PRKCE，它与酒精自我给药有关。值得注意的是，只有少数 SNP（18.4%）与置信度大于 0.75 的基因有关，这强调了需要应用多种方法来为基因座赋予功能。最后，一些先前鉴定的酒精摄入风险基因编码的蛋白质与肝功能有关，并且是药物的靶点，其中一些是治疗肝毒性的候选药物。