Proteome-wide Mendelian randomization and colocalization analysis identify therapeutic targets for stroke
Abstract Background Stroke is a leading cause of death and disability worldwide, yet its treatment still faces significant challenges. Mendelian randomization (MR) has been widely used to discover new biomarkers and therapeutic targets. This study aimed to identify therapeutic targets for stroke wit...
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BMC
2025-07-01
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| Series: | BMC Neurology |
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| Online Access: | https://doi.org/10.1186/s12883-025-04239-9 |
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| author | Xueling Zhao Menghao He Desheng Zhou Zhong Li Lijuan Liu Renyi Yang Xinhua Zhu Cuilan Gong Siyang Yan |
| author_facet | Xueling Zhao Menghao He Desheng Zhou Zhong Li Lijuan Liu Renyi Yang Xinhua Zhu Cuilan Gong Siyang Yan |
| author_sort | Xueling Zhao |
| collection | DOAJ |
| description | Abstract Background Stroke is a leading cause of death and disability worldwide, yet its treatment still faces significant challenges. Mendelian randomization (MR) has been widely used to discover new biomarkers and therapeutic targets. This study aimed to identify therapeutic targets for stroke within the plasma proteome range using MR. Methods We conducted a two-sample MR study, evaluating the causal relationships between 2,940 plasma proteins from the UK Biobank-Proteome-wide Association Study (UKB-PPP) and stroke, with further validation in 4,907 plasma proteins from Iceland. Subsequently, drug target proteins were determined using Bayesian colocalization, Summary data-based Mendelian randomization (SMR), and protein-protein interaction (PPI) network construction to validate the role of selected disease-associated proteins. Results Preliminary MR analysis identified 11 proteins (LPA, FURIN, MST1, FKBPL, SH2B3, MMP12, F11, ITGAV, DDHD2, VSIR and GAS6) significantly associated with stroke or stroke subtypes. Through SMR and colocalization analysis, 4 potential drug target proteins were identified: FURIN as a potential drug target for stroke and any ischemic stroke, F11 as a potential drug target for cardioembolic stroke, DDHD2 and VSIR as potential drug targets for small vessel stroke. It is worth noting that F11 is currently being used in the development of multiple drugs, FURIN is not only associated with stroke but also appears to have abnormal expression in several cardiovascular diseases. Although research on DDHD2 and VSIR in the context of stroke is relatively limited, current findings indicate that DDHD2 is related to synaptic plasticity, while VSIR is associated with microglia and immune responses. Conclusion This study found that the plasma proteins FURIN, F11, DDHD2, and VSIR show promise as potential therapeutic targets for stroke and its subtypes, providing genetic evidence to support precision drug development and insights into the underlying pathological mechanisms of stroke. Clinical trial number Not applicable. |
| format | Article |
| id | doaj-art-afb42e2ac0f44901b465cb1fa62e3bbf |
| institution | Kabale University |
| issn | 1471-2377 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Neurology |
| spelling | doaj-art-afb42e2ac0f44901b465cb1fa62e3bbf2025-08-20T04:01:35ZengBMCBMC Neurology1471-23772025-07-0125111410.1186/s12883-025-04239-9Proteome-wide Mendelian randomization and colocalization analysis identify therapeutic targets for strokeXueling Zhao0Menghao He1Desheng Zhou2Zhong Li3Lijuan Liu4Renyi Yang5Xinhua Zhu6Cuilan Gong7Siyang Yan8The First Hospital of Hunan University of Chinese MedicineThe First Hospital of Hunan University of Chinese MedicineThe First Hospital of Hunan University of Chinese MedicineThe First Hospital of Hunan University of Chinese MedicineThe First Hospital of Hunan University of Chinese MedicineHunan University of Chinese MedicineThe First Hospital of Hunan University of Chinese MedicineThe First Hospital of Traditional Chinese Medicine in Changde, The Changde Affiliated Hospital of Hunan University of Chinese MedicineThe First Hospital of Hunan University of Chinese MedicineAbstract Background Stroke is a leading cause of death and disability worldwide, yet its treatment still faces significant challenges. Mendelian randomization (MR) has been widely used to discover new biomarkers and therapeutic targets. This study aimed to identify therapeutic targets for stroke within the plasma proteome range using MR. Methods We conducted a two-sample MR study, evaluating the causal relationships between 2,940 plasma proteins from the UK Biobank-Proteome-wide Association Study (UKB-PPP) and stroke, with further validation in 4,907 plasma proteins from Iceland. Subsequently, drug target proteins were determined using Bayesian colocalization, Summary data-based Mendelian randomization (SMR), and protein-protein interaction (PPI) network construction to validate the role of selected disease-associated proteins. Results Preliminary MR analysis identified 11 proteins (LPA, FURIN, MST1, FKBPL, SH2B3, MMP12, F11, ITGAV, DDHD2, VSIR and GAS6) significantly associated with stroke or stroke subtypes. Through SMR and colocalization analysis, 4 potential drug target proteins were identified: FURIN as a potential drug target for stroke and any ischemic stroke, F11 as a potential drug target for cardioembolic stroke, DDHD2 and VSIR as potential drug targets for small vessel stroke. It is worth noting that F11 is currently being used in the development of multiple drugs, FURIN is not only associated with stroke but also appears to have abnormal expression in several cardiovascular diseases. Although research on DDHD2 and VSIR in the context of stroke is relatively limited, current findings indicate that DDHD2 is related to synaptic plasticity, while VSIR is associated with microglia and immune responses. Conclusion This study found that the plasma proteins FURIN, F11, DDHD2, and VSIR show promise as potential therapeutic targets for stroke and its subtypes, providing genetic evidence to support precision drug development and insights into the underlying pathological mechanisms of stroke. Clinical trial number Not applicable.https://doi.org/10.1186/s12883-025-04239-9StrokeIschemic strokePlasma proteinsMendelian randomizationDrug targets |
| spellingShingle | Xueling Zhao Menghao He Desheng Zhou Zhong Li Lijuan Liu Renyi Yang Xinhua Zhu Cuilan Gong Siyang Yan Proteome-wide Mendelian randomization and colocalization analysis identify therapeutic targets for stroke BMC Neurology Stroke Ischemic stroke Plasma proteins Mendelian randomization Drug targets |
| title | Proteome-wide Mendelian randomization and colocalization analysis identify therapeutic targets for stroke |
| title_full | Proteome-wide Mendelian randomization and colocalization analysis identify therapeutic targets for stroke |
| title_fullStr | Proteome-wide Mendelian randomization and colocalization analysis identify therapeutic targets for stroke |
| title_full_unstemmed | Proteome-wide Mendelian randomization and colocalization analysis identify therapeutic targets for stroke |
| title_short | Proteome-wide Mendelian randomization and colocalization analysis identify therapeutic targets for stroke |
| title_sort | proteome wide mendelian randomization and colocalization analysis identify therapeutic targets for stroke |
| topic | Stroke Ischemic stroke Plasma proteins Mendelian randomization Drug targets |
| url | https://doi.org/10.1186/s12883-025-04239-9 |
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