Integration of Mendelian Randomization and FAERS Database Analysis Reveals the Association Between Ergotamine and Aortic and Mitral Valve Diseases

To identify potential agents associated with the development of valvular heart diseases (VHD), we employed Mendelian randomization and colocalization analyses to pinpoint genes significantly linked to VHD. A total of 324 genes were found to be positively associated with VHD, among which AGK and TLE5 demonstrated evidence of colocalization. Then, transcriptome data of aortic and mitral valve diseases were retrieved from GEO database. Based on the expression levels of AGK and TLE5, sequencing data for aortic and mitral valve diseases were stratified into two subtypes, respectively. Differentially expressed genes between these subtypes underwent KEGG pathway enrichment analysis. Molecular docking revealed that ergotamine and fosfomycin exhibited the highest binding affinities to AGK and TLE5, respectively. Then, FAERS database was utilized to corroborate the associations between the identified drugs and aortic and mitral valve diseases. Analysis of the FAERS database indicated reporting odds ratios of 13.82 (95% CI: 5.17–36.94) for ergotamine and 2.14 (95% CI: 0.69–6.63) for fosfomycin. For further validation, naratriptan and aztreonam were employed as control drugs. The adjusted odds ratios for ergotamine and fosfomycin were 8.31 (95% CI: 1.61–38.39) and 2.96 (95% CI: 0.84–18.75), respectively, when compared to the control drugs. Finally, human aortic and mitral interstitial cells were isolated and transfected with AGK plasmid. After adding Ly294002 (inhibitor of PI3K-Akt), the western blot results showed that AGK promoted the fibrosis of aortic and mitral interstitial cells via PI3K-Akt signaling pathway. In conclusion, ergotamine may contribute to the development of aortic and mitral valve diseases through the activation of AGK.