Integrative mediation and multi-omics analysis to decode Aortic dissection’s genetic causal phenotype and potential therapeutic targets

Background Aortic dissection(AD) is a fatal cardiovascular emergency associated with inflammation, immunity, and metabolic factors. Understanding the underlying etiology and identifying pathogenic targets of AD is essential for its prevention, accurate diagnosis, and effective treatment. Objective: We sought to elucidate the mediating role of metabolites in the causal relationship between inflammation-related proteins, immune cells, diet and AD. Additionally, we sought to identify potential therapeutic targets for the management of AD. Methods The causal relationship between 91 inflammation-related proteins, 731 immune cells, 239 diet and AD mediated by plasma metabolites were inferred by MR analysis. Furthermore, we conducted multi-omics summary data-based MR (SMR) studies utilizing expression quantitative trait loci (eQTL) and protein quantitative trait loci (pQTL) data to unveil potential risk genes and the pathophysiological mechanisms underlying AD. Results A total of two inflammation-related proteins, 38 immune cells, 12 diet, and 71 plasma metabolites have been identified as causally linked to AD. Mediation analysis revealed the involvement of two distinct pathways in the underlying mechanisms of AD. The pivotal target gene associated with AD, SHMT1, has been pinpointed through SMR study, thereby promoting the development of gene-targeted therapeutic approaches. Conclusion This research thoroughly clarifies the role of inflammation-related proteins, immune cells, and the complex interplay of diet in the pathogenesis of AD. The potential pathways and identified proteins may offer novel insights into the underlying mechanisms of AD, contributing to strategies for its prevention.