Kompleksowa analiza związku między lekami a białkami, sekwencjonowanie komórek i badania na zwierzętach w celu zrozumienia przyczyn ogniskowej epilepsji
Integrative Drug-Target Causal Analysis, Single-Cell Sequencing and In-Vivo Validation for Dissecting Molecular Mechanisms Underlying Focal Epilepsy
W skrócie
Naukowcy zbadali geny, które mogą być związane z rozwojem ogniskowej epilepsji, używając zaawansowanych metod analizy genetycznej i danych z dużych baz medycznych. Znaleźli cztery geny (CASP1, FST, IL10RA i SUCNR1), które mogą wpływać na ryzyko epilepsji - dwa z nich zmniejszają ryzyko choroby, a dwa je zwiększają. Wyniki sugerują, że te cztery geny mogą być dobrymi celami dla nowych leków przeciwko ogniskowej epilepsji.
Oryginalny abstract (angielski)
AIMS: To identify and verify new drug targets for focal epilepsy. METHODS: We combined single-cell expression data from GSE190452, with genetic data from the eQTLGen alliance and utilized expression-associated single nucleotide polymorphism as an instrumental variable in Mendelian randomization analysis to investigate the causal link between gene expression and focal epilepsy risk. Moreover, co-localization analysis was used to evaluate the genetic mediating effect of gene expression. Potential drug interaction mechanisms involving the protein products of key genes were explored using molecular docking technology. The results were verified using an animal model of temporal lobe epilepsy. RESULTS: The results of Mendelian randomization analysis found that four genes (CASP1, FST, IL10RA, and SUCNR1) were significantly associated with focal epilepsy risk in the FinnGen and UK Biobank cohorts. However, only SUCNR1 (odds ratio [OR] = 0.462; 95% confidence interval [95% CI]: 0.240-0.890; p = 0.021) and IL10RA (OR = 0.719; 95% CI: 0.547-0.945; p = 0.018) showed consistent negative correlation, indicating that they may have a protective effect (OR < 1). Meanwhile, CASP1 (OR = 1.260; 95% CI: 1.023-1.553; p = 0.030) and FST (OR = 1.377; 95% CI: 1.044-1.816; p = 0.024) were associated with increased risk (OR > 1). CONCLUSION: CASP1, FST, IL10RA, and SUCNR1 are potential druggable genes and promising therapeutic targets for focal epilepsy treatment.