Identification of prospective novel drug targets for immune thrombocytopenia by integrating plasma proteome
Objectives 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.Methods Genetic instruments for 2923 plasma proteins from the UKBPPP study and ITP data from...
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Taylor & Francis Group
2025-12-01
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| Series: | Hematology |
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| Online Access: | https://www.tandfonline.com/doi/10.1080/16078454.2025.2545645 |
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| author | Wei He Jingcheng Zhang Mingzhe Zhao Jinyong Fang Fang He Caifang Zhao |
| author_facet | Wei He Jingcheng Zhang Mingzhe Zhao Jinyong Fang Fang He Caifang Zhao |
| author_sort | Wei He |
| collection | DOAJ |
| description | Objectives 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.Methods 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).Results 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 P = 1.747 × 10−3) as a risk factor, and NOTCH3 (OR = 0.090; 95% CI 0.019–0.431; adjusted P = 2.593 × 10−2) 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.Discussion and Conclusion 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. |
| format | Article |
| id | doaj-art-bf8d0f7051bc4def86d963d7baaaaf3f |
| institution | DOAJ |
| issn | 1607-8454 |
| language | English |
| publishDate | 2025-12-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | Hematology |
| spelling | doaj-art-bf8d0f7051bc4def86d963d7baaaaf3f2025-08-20T03:04:50ZengTaylor & Francis GroupHematology1607-84542025-12-0130110.1080/16078454.2025.2545645Identification of prospective novel drug targets for immune thrombocytopenia by integrating plasma proteomeWei He0Jingcheng Zhang1Mingzhe Zhao2Jinyong Fang3Fang He4Caifang Zhao5Department of Hematology, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, Zhejiang, People’s Republic of ChinaDepartment of Hematology, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, Zhejiang, People’s Republic of ChinaDepartment of Hematology, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, Zhejiang, People’s Republic of ChinaDepartment of Hematology, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, Zhejiang, People’s Republic of ChinaDepartment of Hematology, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, Zhejiang, People’s Republic of ChinaDepartment of Hematology, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, Zhejiang, People’s Republic of ChinaObjectives 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.Methods 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).Results 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 P = 1.747 × 10−3) as a risk factor, and NOTCH3 (OR = 0.090; 95% CI 0.019–0.431; adjusted P = 2.593 × 10−2) 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.Discussion and Conclusion 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.https://www.tandfonline.com/doi/10.1080/16078454.2025.2545645Mendelian randomizationimmune thrombocytopeniaplasma proteindrug targetgenome-wide studyprotein-protein interaction |
| spellingShingle | Wei He Jingcheng Zhang Mingzhe Zhao Jinyong Fang Fang He Caifang Zhao Identification of prospective novel drug targets for immune thrombocytopenia by integrating plasma proteome Hematology Mendelian randomization immune thrombocytopenia plasma protein drug target genome-wide study protein-protein interaction |
| title | Identification of prospective novel drug targets for immune thrombocytopenia by integrating plasma proteome |
| title_full | Identification of prospective novel drug targets for immune thrombocytopenia by integrating plasma proteome |
| title_fullStr | Identification of prospective novel drug targets for immune thrombocytopenia by integrating plasma proteome |
| title_full_unstemmed | Identification of prospective novel drug targets for immune thrombocytopenia by integrating plasma proteome |
| title_short | Identification of prospective novel drug targets for immune thrombocytopenia by integrating plasma proteome |
| title_sort | identification of prospective novel drug targets for immune thrombocytopenia by integrating plasma proteome |
| topic | Mendelian randomization immune thrombocytopenia plasma protein drug target genome-wide study protein-protein interaction |
| url | https://www.tandfonline.com/doi/10.1080/16078454.2025.2545645 |
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