Causality of blood metabolites and metabolic pathways on peripheral arteriosclerosis: a Mendelian randomization study.

Background: Peripheral arteriosclerosis is caused by any atherosclerosis outside the heart and brain. However, the underlying biological mechanisms are not fully understood. This study aims to explore the causal relationship between blood metabolites and peripheral arteriosclerosis.

Methods: A Mendelian randomization (MR) analysis was implemented to estimate the causality of blood metabolites on peripheral arteriosclerosis. A genome-wide association study (GWAS) of 1,400 metabolites was used as the exposure, whereas two different GWAS datasets of peripheral arteriosclerosis were the outcomes. Inverse-variance weighted (IVW) was the main analysis of causal analysis. MR-Egger, the simple mode, weighted median and weighted mode were used to increase the stability and robustness of the results. Cochran Q test, MR-Egger intercept test, the funnel plot, and MR-Pleiotropy RESidual Sum and Outlier were used for sensitivity analyses. Furthermore, metabolic pathway enrichment analysis was performed using MetaboAnalyst5.0.

Results: In this MR study, eight blood metabolites have a strong causal relationship with peripheral arteriosclerosis, including 1-myristoyl-2-arachidonoyl-GPC (14:0/20:4), 1-palmitoyl-2-arachidonoyl-gpc (16:0/20:4n6), 1-(1-enyl-stearoyl)-2-arachidonoyl-GPE, 1-palmitoyl-2-dihomo-linolenoyl-GPC, Gamma-glutamylleucine, Deoxycholic acid glucuronide and two named X- (X-24546, X-26111). In addition, five important metabolic pathways in peripheral arteriosclerosis were identified through metabolic pathway analysis.

Conclusion: This study provides evidence for the causal relationship between blood metabolites and peripheral arteriosclerosis, and these eight blood metabolites provide new perspectives for screening and prevention of peripheral arteriosclerosis in the future.