Causal Effect of Multi-cohort Circulating Proteome on the Risk of Aortic Aneurysm: A Mendelian Randomization Study

BackgroundThe pathogenesis of aortic aneurysm (AA) remains unclear, and there are no effective therapeutic drugs or targets. Circulating plasma proteins are considered biomarkers of AA and potential therapeutic targets for AA. This study aimed to systematically evaluate the causal effects of plasma proteins on AA using a multi-cohort Mendelian randomization (MR) approach. MethodsProtein quantitative trait loci (pQTLs) was obtained from 9 published proteome genome-wide association studies (GWAS) and AA GWAS data from the FinnGen cohort. Independent pQTLs were selected as instrumental variables (IVs). Two-sample MR analysis was performed using inverse-variance weighted, MR-Egger regression, weighted median, weighted mode, and simple mode methods. Heterogeneity and pleiotropy were assessed using Cochrans Q test, I{superscript 2} statistic, MR-Egger intercept, MR-PRESSO, and Leave-one-out analysis. Steiger filtering was used to test the causal direction. Colocalization analysis and pQTL-eQTL overlap assessment were conducted to validate the findings. Pathway enrichment and drug target analyses were performed to explore the biological and clinical implications of the MR results. ResultsA total of 8,285 pQTLs for 4,421 proteins were retained as IVs. Using cis-pQTLs for IVs, MR analysis identified 154 proteins causally associated with TAA (76 protective factors and 78 risk factors) and 211 proteins with AAA (112 protective factors and 99 risk factors). Using cis-pQTLs+trans-pQTLs for IVs, MR analysis identified 236 proteins causally associated with TAA (113 protective factors and 123 risk factors) and 309 proteins with AAA (143 protective factors and 166 risk factors). The MR results showed no significant heterogeneity or pleiotropy. Steiger filtering confirmed the causal direction from circulating proteins to AA. Colocalization analysis found evidence of shared causal variants between multiple proteins and AA. The majority of AA-associated proteins had pQTLs overlapping with blood eQTLs or proxy eQTLs. Pathway enrichment analysis revealed that these proteins were involved in stress response, immune regulation, cytokine-cytokine receptor interaction, metabolic processes and so on. Nearly two-thirds of the causally related proteins were classified as druggable or potentially druggable targets. ConclusionsThis study identified a large number of potentially novel pathogenic proteins and therapeutic targets for AA, providing important references for elucidating the molecular pathogenesis of AA and advancing drug development.