整合多组学全转录组分析以鉴定糖尿病视网膜病变中的新型治疗药物靶点。

Integration of multi-omics transcriptome-wide analysis for the identification of novel therapeutic drug targets in diabetic retinopathy.

作者信息

Yi Guoguo, Li Zhengran, Sun Yuxin, Ma Xinyu, Wang Zijin, Chen Jinken, Cai Dong, Zhang Ziran, Chen Zejun, Wu Fanye, Cao Mingzhe, Fu Min

机构信息

Department of Ophthalmology, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China.

Department of Ophthalmology, Zhujiang Hospital, Southern Medical University, 253 Industrial Avenue, Guangzhou, 510282, China.

出版信息

J Transl Med. 2024 Dec 24;22(1):1146. doi: 10.1186/s12967-024-05856-7.

DOI:10.1186/s12967-024-05856-7

PMID:39719581

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11667901/

Abstract

BACKGROUND

Diabetic retinopathy (DR) is the most important complication of Type 2 Diabetes (T2D) in eyes. Despite its prevalence, the early detection and management of DR continue to pose considerable challenges. Our research aims to elucidate potent drug targets that could facilitate the identification of DR and propel advancements in its therapeutic strategies.

METHODS

A broad multi-omics exploration of DR was presented to decipher the drug targets of DR and proliferative diabetic retinopathy (PDR). Transcriptome-Wide Association Studies (TWAS), fine-mapping and conditional analysis were applied to unearth potential tissue-specific gene associations with DR. Summary Data-based Mendelian Randomization (SMR) provided secondary analysis of high confidence genes. Cis-instrument of druggable genes were extracted from the eQTLGen Consortium and PsychENCODE, facilitating drug-target MR supported by colocalization analysis. Phenome-Wide Association Studies (PheWAS) was conducted on the high confidence genes. Metabolomic and immunomic MR-profiling further augmented our research as complement.

RESULTS

TWAS identified multiple robust genetic loci in both DR and PDR (WFS1, RPS26, and SRPK1) through genetic associations across different tissues. Meanwhile, we have delineated both the commonalities and discrepancies between DR and PDR at the transcriptomic level, represented by DCLRE1B as the hub gene that DR progressed into PDR. SMR revealed 92 key DR-related genes and 55 PDR-related genes. HLA-DQ family genes have a frequent occurrence, while RPS26, WFS1 and SRPK1 were validated as the genetic network's linchpins. Drug-target MR casted ERBB3 and SRPK1 as candidate effector genes for DR and PDR susceptibility. In addition, metabolomics and immunomics analyses also revealed multifaceted pathogenic factors for DR.

CONCLUSIONS

Our research offers targeted therapeutic insights for early-stage DR and facilitates multi-omic comparisons of it and PDR.

摘要

背景

糖尿病视网膜病变（DR）是2型糖尿病（T2D）最重要的眼部并发症。尽管其发病率很高，但DR的早期检测和管理仍然面临相当大的挑战。我们的研究旨在阐明有效的药物靶点，以促进DR的识别并推动其治疗策略的进步。

方法

对DR进行广泛的多组学探索，以破译DR和增殖性糖尿病视网膜病变（PDR）的药物靶点。应用全转录组关联研究（TWAS）、精细定位和条件分析来挖掘与DR潜在的组织特异性基因关联。基于汇总数据的孟德尔随机化（SMR）对高置信度基因进行二次分析。从eQTLGen联盟和PsychENCODE中提取可药物化基因的顺式工具，通过共定位分析促进药物靶点孟德尔随机化。对高置信度基因进行全表型关联研究（PheWAS）。代谢组学和免疫组学MR分析作为补充进一步加强了我们的研究。

结果

TWAS通过不同组织的基因关联在DR和PDR中均鉴定出多个强大的遗传位点（WFS1、RPS26和SRPK1）。同时，我们在转录组水平上描绘了DR和PDR之间的共性和差异，以DCLRE1B作为DR进展为PDR的枢纽基因。SMR揭示了92个关键的DR相关基因和55个PDR相关基因。HLA-DQ家族基因频繁出现，而RPS26、WFS1和SRPK1被验证为遗传网络的关键节点。药物靶点孟德尔随机化将ERBB3和SRPK1确定为DR和PDR易感性的候选效应基因。此外，代谢组学和免疫组学分析也揭示了DR的多方面致病因素。