Lipid Metabolic Mediators Bridge Ischemic Heart Disease and Amyotrophic Lateral Sclerosis

While epidemiological studies have linked cardiovascular disease (CVD) and amyotrophic lateral sclerosis (ALS), the causal pathways remain unclear. This study aims to clarify the causal relationship between CVD and ALS, with a focus on lipid metabolism as a potential mediator. We conducted a bidirectional two-sample Mendelian randomization (MR) analysis to investigate the causal relationship between CVD and ALS. Furthermore, we utilized mediation MR, summary-data-based MR analysis (SMR), the Kyoto Encyclopedia of Genes and Genomes (KEGG), Gene Ontology (GO) pathway analysis, miRNA interaction prediction analysis, and protein-protein interaction (PPI) studies to validate the mediating effect of lipid metabolism on the risk of CVD and ALS onset, as well as to predict potential signaling pathways and mechanisms. The MR analysis revealed a significant association between CVD, particularly IHD, and an increased risk of ALS. Mediation analysis indicated that the level of sphingomyelin (d34:0) in serum may mediate the effect of IHD on ALS, along with the identification of seven additional types of plasma metabolites. Furthermore, KEGG and GO analyses highlighted lipid metabolism pathways, including "cholesterol metabolism" and the "phospholipid metabolic process." Additionally, miRNA interaction prediction analysis identified MFGE8 as a potential therapeutic target. Our study identifies IHD as a vascular risk factor for ALS, driven by lipid metabolic dysregulation. The identification of sphingomyelin (d34:0) and MFGE8 as key mediators in lipid metabolic dysregulation offers potential preventive and therapeutic strategies for CVD patients at elevated risk of ALS.