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Identification and validation of druggable targets for cataract using mendelian randomization: functional insights
1Department of Ophthalmology, Fujian Provincial Geriatric Hospital, Fujian Provincial Hospital North Branch, Fuzhou, China.
Objective:
To identify druggable genes associated with cataract and investigate their functional roles under oxidative stress, thereby providing potential therapeutic targets.
Methods:
Multi-omics data were integrated, and expression quantitative trait loci (eQTL) and protein quantitative trait loci (pQTL) analyses, along with Mendelian randomization (MR), were performed to assess the causal relationships between gene/protein expression and cataract risk. Phenome-wide association studies (PheWAS), the creation of protein-protein interaction networks, drug prediction, and molecular docking were further performed to evaluate their functional relevance and potential for drug development. In addition, an oxidative stress model was established by treating SRA01/04 lens epithelial cells with H2O2, and cell viability, proliferation, apoptosis, and hub gene expression were assessed using CCK8, EdU, flow cytometry, and qPCR.
Results:
Among 2,532 drug-associated genes, 35 eQTL genes and 31 pQTL genes were identified, with DKK3, GSTM1, and KIR2DS4 showing significant associations in both analyses. PheWAS revealed no major adverse effects, and drug prediction and molecular docking suggested GSTM1 as the most promising target. In vitro, H2O2 suppressed SRA01/04 cell viability and proliferation while promoting apoptosis in a dose-dependent manner. qPCR results showed that oxidative stress upregulated DKK3 and downregulated GSTM1 expression, both in a dose-dependent manner, consistent with MR findings, supporting DKK3 as a risk factor and GSTM1 as a protective factor for cataract.
Conclusion:
This study identified and validated DKK3 and GSTM1 as key genes in cataract pathogenesis. By integrating genetic analyses with functional experiments, our findings provide new insights into the molecular mechanisms of cataract and establish a theoretical basis for drug development and repurposing.
Insights
This study identifies DKK3 and GSTM1 as key genes in cataract development. Findings support DKK3 as a risk factor and GSTM1 as protective, offering targets for new cataract therapies.
Area of Science:
- Genetics and Molecular Biology
- Ophthalmology
- Pharmacology
Background:
- Cataract is a leading cause of blindness, driven by complex genetic and environmental factors.
- Oxidative stress is implicated in cataract pathogenesis, but specific molecular targets remain elusive.
- Identifying druggable genes is crucial for developing novel therapeutic strategies.
Purpose of the Study:
- To identify genes associated with cataract risk that can be targeted by drugs.
- To investigate the functional roles of these genes, particularly under oxidative stress conditions.
- To provide a scientific basis for drug development and repurposing for cataract treatment.
Main Methods:
- Integrated multi-omics data, including expression quantitative trait loci (eQTL) and protein quantitative trait loci (pQTL) analyses.
- Utilized Mendelian randomization (MR), Phenome-wide association studies (PheWAS), and protein-protein interaction networks.
- Established an oxidative stress model in lens epithelial cells to assess gene expression and cellular responses.
Main Results:
- Identified 35 eQTL and 31 pQTL genes; DKK3 and GSTM1 showed significant associations.
- DKK3 was identified as a risk factor, while GSTM1 emerged as a protective factor for cataract.
- Oxidative stress upregulated DKK3 and downregulated GSTM1 expression in lens epithelial cells.
Conclusions:
- DKK3 and GSTM1 are validated as key genes in cataract pathogenesis.
- Findings offer new insights into cataract molecular mechanisms and oxidative stress.
- This research provides a theoretical foundation for developing and repurposing drugs for cataract.
