He Wei, Zhang Jingcheng, Zhao Mingzhe, Fang Jinyong, He Fang, Zhao Caifang
Department of Hematology, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, Zhejiang, People's Republic of China.
Hematology. 2025 Dec;30(1):2545645. doi: 10.1080/16078454.2025.2545645. Epub 2025 Aug 14.
The etiology of immune thrombocytopenia (ITP) is heterogeneous and intricate, with some unresponsive to current treatments. We used Mendelian randomization (MR) to identify new therapeutic targets.
Genetic instruments for 2923 plasma proteins from the UKBPPP study and ITP data from a genome-wide study (GWAS) by the FinnGen project were used to perform MR analyses. Data sets from the deCODE project and eQTLGen consortium were used to perform replication analysis. A protein-protein interactions PPI) network was employed to predict the relationship between the identified proteins and drug targets of current clinical medicines. Potential side effects of targeting these proteins were predicted using Phenome-wide association studies (PheWAS).
Co-localization analysis identified 27 plasma proteins associated with ITP. Summary data-based MR (SMR) analysis and heterogeneity in dependent instrument (HEIDI) tests indicated that four proteins (AGER, FKBPL, NOTCH3, and DNAJC21) are correlated with ITP. Replication analysis validated two: DNAJC21 (OR = 2.417; 95% CI 1.391-4.200; adjusted = 1.747 × 10) as a risk factor, and NOTCH3 (OR = 0.090; 95% CI 0.019-0.431; adjusted = 2.593 × 10) as protective. The PPI network and protein druggability assessment showed that both proteins were related to current drug targets of ITP. PheWAS indicated that drugs targeting DNAJC21 or NOTCH3 had few side effects.
Numerous efforts are still needed to identify novel therapies for treatment of ITP. These results indicate that DNAJC21 and NOTCH3 could be prospective therapeutic targets for managing ITP.
免疫性血小板减少症（ITP）的病因复杂多样，部分患者对当前治疗无反应。我们采用孟德尔随机化（MR）方法来确定新的治疗靶点。
利用英国生物银行血浆蛋白质组计划（UKBPPP）研究中的2923种血浆蛋白的遗传工具以及芬兰基因计划（FinnGen）项目全基因组研究（GWAS）中的ITP数据进行MR分析。使用来自deCODE项目和eQTLGen联盟的数据集进行重复分析。采用蛋白质-蛋白质相互作用（PPI）网络预测已鉴定蛋白质与当前临床药物靶点之间的关系。使用全表型关联研究（PheWAS）预测靶向这些蛋白质的潜在副作用。
共定位分析确定了27种与ITP相关的血浆蛋白。基于汇总数据的MR（SMR）分析和依赖工具异质性（HEIDI）检验表明，四种蛋白质（AGER、FKBPL、NOTCH3和DNAJC21）与ITP相关。重复分析验证了两种：DNAJC21作为危险因素（OR = 2.417；95%CI 1.391 - 4.200；校正后 = 1.747×10），NOTCH3作为保护因素（OR = 0.090；95%CI 0.019 - 0.431；校正后 = 2.593×10）。PPI网络和蛋白质可成药评估表明这两种蛋白质均与ITP当前的药物靶点相关。PheWAS表明靶向DNAJC21或NOTCH3的药物副作用较少。
仍需付出诸多努力来确定治疗ITP的新疗法。这些结果表明，DNAJC21和NOTCH3可能是治疗ITP的潜在治疗靶点。
