Reveal a risk and potential mechanism for keratoconus progression with isotretinoin: Toxicogenomic, transcriptomics and real-world evidence insights
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Published on: November 12, 2015
Tao Tao1, Yunyi Peng2, Meiling Zhao3
1Eye Institute & Affiliated Xiamen Eye Center &The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361102, China.
Purpose:
Limited clinical data and unstable animal models hinder understanding isotretinoin-induced keratoconus. We addressed this by integrating pharmacovigilance with computational approaches.
Methods:
Isotretinoin-associated ocular surface adverse events were extracted from the FDA Adverse Event Reporting System (FAERS). Disproportionality analyses detected pharmacovigilance signals, and age confounding bias was assessed with multivariable logistic regression. Network toxicology and transcriptomics defined candidate targets. Enrichment analyses implicated biological processes and pathways. Key targets were refined via random forest, SVM-RFE, and LASSO regression. Single-cell transcriptomic profiling delineated the cell-type-specific expression patterns of the four targets in corneal stromal cells, epithelial cells, and immune cell subsets. Computer-Aided Drug Design examined the molecular binding mechanisms between isotretinoin and the three identified target proteins.
Results:
Keratoconus is strongly associated with isotretinoin (log10ROR = 1.32, 95 % CI = 1.10-1.56), supported across multiple algorithms. Age showed no significant association (OR = 0.99, 95 % CI: 0.92-1.04, p = 0.795). 19 overlapping genes identified, predominantly involved in extracellular matrix processes such as cell migration and growth factor binding. Machine learning prioritized key molecular markers: IL1A, THBS1, IGFBP3, and TGFB1. Single-cell transcriptomics delineated IGFBP3 and TGFB1 enrichment in corneal epithelial cells, IL1A in immune cells, and THBS1 in both stromal and immune compartments. Molecular docking and dynamics demonstrate that isotretinoin can stably bind to the three target proteins, maintaining stable binding conformations and interactions throughout the simulation period.
Conclusions:
This integrative analysis identifies a robust pharmacovigilance signal between isotretinoin and keratoconus and warrants further clinical and experimental investigation.
Insights
Isotretinoin is strongly linked to keratoconus, a serious eye condition. This study used computational methods to identify key molecular targets, suggesting a need for further clinical research into this association.
Area of Science:
- Ophthalmology
- Pharmacovigilance
- Computational Biology
Background:
- Limited clinical data and animal models hinder understanding of isotretinoin-induced keratoconus.
- Pharmacovigilance and computational approaches offer novel insights.
Purpose of the Study:
- To investigate the association between isotretinoin and keratoconus using integrated pharmacovigilance and computational methods.
- To identify potential molecular targets and pathways involved in isotretinoin-induced ocular surface toxicity.
Main Methods:
- Extracted ocular adverse events from FDA FAERS database.
- Performed disproportionality analyses and multivariable logistic regression to detect safety signals and assess bias.
- Utilized network toxicology, transcriptomics, and machine learning to identify and prioritize key molecular targets (IL1A, THBS1, IGFBP3, TGFB1).
- Conducted single-cell transcriptomics and molecular docking to elucidate cell-type-specific expression and binding mechanisms.
Main Results:
- A significant pharmacovigilance signal for isotretinoin-associated keratoconus was detected (log10ROR = 1.32).
- Age was not found to be a confounding factor.
- Identified 19 overlapping genes involved in extracellular matrix processes; prioritized IL1A, THBS1, IGFBP3, and TGFB1.
- Delineated cell-type-specific expression patterns and confirmed stable binding of isotretinoin to target proteins.
Conclusions:
- This study establishes a robust association between isotretinoin and keratoconus.
- The findings warrant further clinical and experimental investigation into the underlying mechanisms.
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