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APOE and Cerebral Microbleeds: Insights Into Causal Proteins and Therapeutic Targets
Lei Yang1, Jian-Lan Zhao1,2, Jie Song1
1Department of Neurosurgery & Neurocritical care, Huashan Hospital, Fudan University, Shanghai, China.
Background:
Cerebral microbleeds (CMBs) are small chronic brain hemorrhages that can be linked to cognitive decline and stroke risk. Understanding the underlying genetic and proteomic mechanisms can enhance therapeutic interventions. This study aimed to explore the relationship between circulating proteins (cis-pQTLs) and CMBs using Mendelian randomization (MR) and colocalization analysis, along with protein-protein interaction (PPI) network construction and the evaluation of lifestyle factors influencing CMB-related proteins.
Methods:
A two-sample MR approach was employed to investigate potential causal relationships between protein levels and CMB risk using cis-pQTLs as instrumental variables. Colocalization analysis was conducted to assess whether the same genetic variants influence both circulating proteins and CMB susceptibility. Additionally, a PPI network was built to prioritize therapeutic targets, and drug efficacy was evaluated using known protein targets. A systematic MR analysis examined the impact of 17 healthy lifestyle factors on CMB-related proteins.
Results:
MR analysis revealed an association between 79 plasma proteins and CMBs, with one protein remaining significant after false discovery rate correction. Colocalization analysis identified APOE as a causal protein for CMBs, supported by a strong posterior probability (PP4 = 0.996). PPI network analysis highlighted the potential bleeding risks of antithrombotic medications in CMB pathogenesis and Rosuvastatin. Furthermore, MR analysis showed that dietary factors, particularly cooked vegetable intake, were associated with APOE-related pathways, though these findings warrant cautious interpretation regarding lifestyle modifications.
Conclusions:
This study provides evidence for a causal relationship between circulating proteins and CMBs, with APOE identified as a key factor. The identification of coagulation-related proteins highlights the potential risks of antithrombotic medications in CMB pathogenesis. Lifestyle factors may influence protein-mediated CMB risk, suggesting avenues for future research into gene-environment interactions.
Insights
Cerebral microbleeds (CMBs) are linked to circulating proteins, with APOE identified as a causal factor. This research explores protein-related risks and lifestyle influences on CMBs, aiding future therapeutic strategies.
Area of Science:
- Genetics and Proteomics
- Neuroscience
- Cardiovascular Research
Background:
- Cerebral microbleeds (CMBs) are associated with cognitive decline and stroke risk.
- Understanding genetic and proteomic factors is crucial for developing effective CMB treatments.
- This study investigates the link between circulating proteins and CMBs.
Purpose of the Study:
- To explore the relationship between circulating proteins and CMBs using Mendelian randomization (MR).
- To identify causal proteins and pathways involved in CMB pathogenesis.
- To evaluate the influence of lifestyle factors on CMB-related proteins.
Main Methods:
- A two-sample MR approach utilizing cis-pQTLs as instrumental variables.
- Colocalization analysis to confirm shared genetic influences on proteins and CMBs.
- Protein-protein interaction (PPI) network construction and analysis of lifestyle factors.
Main Results:
- MR analysis identified 79 plasma proteins associated with CMBs; one remained significant post-correction.
- APOE was identified as a causal protein for CMBs (PP4 = 0.996) via colocalization.
- PPI network suggested bleeding risks with antithrombotics and Rosuvastatin; dietary factors showed links to APOE pathways.
Conclusions:
- Evidence supports a causal link between circulating proteins and CMBs, with APOE as a key mediator.
- Coagulation-related proteins highlight potential risks of antithrombotic medications in CMBs.
- Gene-environment interactions involving lifestyle factors may influence protein-mediated CMB risk.
