Systematic Mendelian Randomization Exploring Druggable Genes for Hemorrhagic Strokes.
Lun-Zhe Yang1, Yong Yang1, Chuan Hong1
1Department of Neurosurgery, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China.
Molecular Neurobiology
|July 8, 2024
Summary
This study used Mendelian randomization to identify six druggable genes linked to hemorrhagic stroke. Inhibiting specific genes like TNFSF12, SLC22A4, and SPARC may prevent strokes and reduce related cardiovascular risks.
Area of Science:
- Genetics
- Pharmacology
- Neurology
Background:
- Hemorrhagic stroke presents significant morbidity and mortality with limited preventive drugs.
- Mendelian randomization (MR) offers a genetic approach to enhance drug development success rates.
Purpose of the Study:
- To systematically identify druggable genes associated with hemorrhagic stroke using MR analysis.
- To explore potential therapeutic targets and their mechanisms for hemorrhagic stroke prevention.
Main Methods:
- Conducted summary-data-based and two-sample MR analyses across multiple gene databases.
- Assessed associations with intracranial aneurysm and intracerebral hemorrhage, including subtypes.
- Validated identified genes through colocalization and analyzed potential cardiovascular side effects.
Main Results:
- Identified 56 genes significantly impacting hemorrhagic stroke incidence.
- Pinpointed six druggable genes: TNFSF12, SLC22A4, SPARC, KL, RELT, and ADORA3.
- Demonstrated that inhibiting TNFSF12, SLC22A4, and SPARC may reduce risks of various hemorrhagic strokes, with hypertension as a potential mechanism.
Conclusions:
- Six druggable genes are associated with hemorrhagic stroke risk.
- Targeted inhibition of TNFSF12, SLC22A4, and SPARC shows promise for hemorrhagic stroke prevention.
- Potential side effects, including ischemic stroke, warrant further investigation.
