Systematic Mendelian randomization of the human plasma proteome to identify therapeutic targets linking aging and frailty to perioperative delirium

BACKGROUND: Perioperative delirium is a growing concern in the aging population, posing significant risks to frail elderly patients. While frailty is associated with delirium, the underlying mechanisms remain unclear. METHODS: We conducted an analysis of data derived from 3788 plasma proteins in a protein quantitative trait locus (pQTL) study encompassing 4709 participants. Utilizing Mendelian randomization (MR) in conjunction with genome-wide association study (GWAS) data, we identified proteins that exhibit significant associations with delirium. Additionally, we investigated the bidirectional relationship between delirium and aging-related indicators, such as the frailty index (FI), Intrinsic Epigenetic Age Acceleration (IEAA), PhenoAge, and life expectancy. This was achieved through mediation analysis and Bayesian colocalization to assess the intermediary effects of these indicators. Finally, we assessed the therapeutic potential of the identified proteins via molecular docking studies. RESULTS: MR analysis revealed causal relationships between delirium and several aging-related indicators, including FI, IEAA, PhenoAge, and life expectancy. Eleven proteins were causally associated with delirium. Mediation analysis showed that the effects of HIBCH and IMPAD1 on delirium were mediated by PhenoAge, while IEAA mediated the effect of MICB. MST1's effect on delirium was mediated by FI and life expectancy. Bayesian colocalization confirmed strong associations between HIBCH, MST1, and delirium. Molecular docking studies indicated that MST1 and HIBCH exhibited low binding energies with midazolam and dexmedetomidine, suggesting their potential as therapeutic targets. CONCLUSION: HIBCH and MST1 are key players in delirium pathophysiology and represent promising therapeutic candidates. Their involvement in delirium warrants further investigation in clinical research.