Identifying therapeutic targets for erectile dysfunction in the European population using genome-wide Mendelian
Peng Guo1, Hongjian Zhang1, Rong Cao1
1Department of Oncology and Vascular Interventional Radiology, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361000, Fujian, China.
Background:
Erectile dysfunction (ED) is a prevalent condition with current treatments limited by suboptimal efficacy and adverse effects. Mendelian randomization (MR) offers a promising approach to identify potential genetic targets for novel therapies.
Aim:
We performed a genome-wide MR study on druggable genes to find ED therapies.
Methods:
We collected data on drug-targetable genes and their impact on blood expression quantitative trait loci (eQTLs). Using two-sample MR with genome-wide association studies data, we pinpointed genes linked to ED and conducted enrichment analysis. We also built protein networks and predicted drugs to support treatment development.
Outcomes:
This comprehensive strategy provides a robust framework for the advancement of more efficacious and precisely targeted treatments for ED.
Results:
The MR analysis identified 124 genes significantly associated with ED. Enrichment analysis revealed these genes are involved in signal transduction, protein phosphorylation, plasma membrane, cytoplasm, ATP binding, and the PI3K-Akt signaling pathway. We identified the top 10 hub genes: PRKCA, IFNG, ITGB1, PPARG, PTK2, LAMA5, BCL2L1, CD3D, CD3E, and CD27. Our study highlighted three potential drugs targeting three of these hub genes: benztropine for CD27, teplizumab for CD3E, and natalizumab for ITGB1.
Clinical Translation:
The study identifies high-priority targets for ED therapy, including approved drugs amenable to rapid repurposing trials.
Strengths And Limitations:
Multi-omics integration enhanced causal validity; drug predictions leveraged existing therapeutic knowledge. Tissue-specific expression quantitative trait loci confounders and lack of experimental validation for prioritized drugs require caution.
Conclusion:
This work advances ED research by mapping druggable genes (PRKCA, IFNG, ITGB1) and pathways via MR, offering precision medicine opportunities and actionable drug repurposing candidates.
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