Exploring Targets for Heart Failure Using Mendelian Randomization, Colocalization, Summary Data-based Mendelian Randomization, and Drug Prediction.

摘要

Heart failure (HF) is a prevalent cardiovascular disease that significantly impairs quality of life in its advanced stages. Despite a variety of current treatment strategies, the disease burden of HF remains significant. Therefore, exploring novel therapeutic targets is urgently needed. This study utilized Mendelian randomization (MR) to evaluate the causal relationships between druggable genes and HF. Colocalization analysis and summary data-based Mendelian randomization (SMR) were conducted to further validate the relationship between them. Finally, 8 potential therapeutic targets for HF were identified, including 4 risk factors (CYP11A1, GALT, KCNH2, and METRN) and 4 protective factors (APOM, CHD4, IL11RA, and LPAR5). The GO enrichment, KEGG enrichment, and protein-protein interaction (PPI) network analysis indicated that these genes were primarily involved in metabolic regulation and cardiac electrophysiological processes. Moreover, potential drugs targeting these targets were identified using drug prediction and molecular docking, including mitotane, Adehl, Benzofurans, 1,3-Di-o-tolylguanidine, 96-69-5, and bromoenol lactone. Furthermore, PCR results also demonstrated that mitotane might be associated with CYP11A1 and KCNH2. Drugs designed based on these potential therapeutic targets may offer higher success rates and improve clinical outcomes.