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PRCP is a promising drug target for intracranial aneurysm rupture supported via multi-omics analysis.
Wu, Jinghao; Mei, Yunyun; Li, XinYu; Yu, Wen-Kai; Zhou, Zi Han; Yang, Yinghao; Niu, Pengpeng; Wang, Yunchao; Shi, Chang-He; Zhu, Hanghang; He, Wenjun; Gao, Yuan; Xu, Yuming; Li, Yusheng.
Afiliación
  • Wu J; Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
  • Mei Y; Department of Neurosurgery, Fudan University Shanghai Cancer Center, Shanghai, Shanghai, China.
  • Li X; The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
  • Yu WK; Department of Neurology, Zhengzhou University, Zhengzhou, Henan, China.
  • Zhou ZH; Reproductive Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
  • Yang Y; Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
  • Niu P; Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
  • Wang Y; Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
  • Shi CH; Department of Neurology, Zhengzhou University, Zhengzhou, Henan, China.
  • Zhu H; Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
  • He W; The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
  • Gao Y; Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
  • Xu Y; Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
  • Li Y; NHC Key Laboratory of Prevention and treatment of Cerebrovascular Disease, zhengzhou, henan, People's Republic of China.
Stroke Vasc Neurol ; 2024 Aug 24.
Article en En | MEDLINE | ID: mdl-39181687
ABSTRACT

BACKGROUND:

Cerebral aneurysms are life-threatening cerebrovascular disorders. Currently, there are no effective treatments for preventing disease progression. Mendelian randomisation (MR) is widely used to repurify licensed drugs and identify new therapeutic targets. Therefore, this study aims to investigate effective drug targets for preventing the formation and rupture of cerebral aneurysms and analyse their potential mechanisms.

METHODS:

We performed a comprehensive study integrating two-sample MR analysis, colocalisation analysis and summary data-based Mendelian randomisation (SMR) to assess the causal effects of blood and brain druggable cis-expression quantitative trait loci (cis-eQTLs) on intracranial aneurysm (IA), unruptured intracranial aneurysm (UIA) and subarachnoid haemorrhage of IA rupture (SAH). Druggable genes were obtained from the study by Chris Finan et al, cis-eQTLs from the eQTLGen and PsychENCODE consortia. Results were validated using proteomic and transcriptomic data. Single-gene functional analyses probed potential mechanisms, culminating in the construction of a drug-gene regulation network.

RESULTS:

Through the MR analysis, we identified four potential drug targets in the blood, including prolylcarboxypeptidase (PRCP), proteasome 20S subunit alpha 4 (PSMA4), LTBP4 and GPR160 for SAH. Furthermore, two potential drug targets (PSMA4 and SLC22A4) were identified for IA and one potential drug target (KL) for UIA after accounting for multiple testing (P(inverse-variance weighted)<8.28e-6). Strong evidence of colocalisation and SMR analysis confirmed the relevance of PSMA4 and PRCP in outcomes. Elevated PRCP circulating proteins correlated with a lower SAH risk. PRCP gene expression was significantly downregulated in the disease cohort.

CONCLUSIONS:

This study supports that elevated PRCP gene expression in blood is causally associated with the decreased risk of IA rupture. Conversely, increased PSMA4 expression in the blood is causally related to an increased risk of IA rupture and formation.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Stroke Vasc Neurol Año: 2024 Tipo del documento: Article País de afiliación: China Pais de publicación: Reino Unido
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Stroke Vasc Neurol Año: 2024 Tipo del documento: Article País de afiliación: China Pais de publicación: Reino Unido