Causality of genetically determined serum metabolites on thoracic and abdominal aortic aneurysm: Mendelian randomization study

Background Aortic aneurysms (AA), including thoracic (TAA) and abdominal (AAA) types, are life-threatening conditions with complex and poorly understood mechanisms. Metabolic alterations, particularly in amino acid and energy metabolism, have been linked to AA, but their roles remain unclear due to limited and confounded observational evidence. Objective This research aimed to comprehensively investigate the potential causal links between serum metabolites and the development of thoracic (TAA) and abdominal (AAA) aortic aneurysms. Methods We analyzed serum metabolites from the Metabolomics data, using datasets of 353,049 individuals for TAA (3510 cases) and 353,087 individuals for AAA (3548 cases). Mendelian randomization (MR) techniques, including MR-Egger regression and inverse-variance weighting (IVW), assessed causality, with heterogeneity tested using Cochran's Q and I 2 statistics, and pleiotropy via the MR-Egger intercept. Sensitivity was further checked through leave-one-out analysis. SNP annotations identified genes linked to TAA and AAA, and metabolic pathways were also analyzed. Results Nine metabolites were causally linked to TAA, with three as risk factors, while 18 metabolites were associated with AAA, including eight risk factors. 3-dehydrocarnitine showed contrasting effects, acting as a risk factor for TAA ( OR = 2.704; P = 0.031 ) and a protective factor for AAA (OR = 0.303; P = 0.025). Pathway analysis revealed TAA-related pathways such as “Pyruvaldehyde degradation” and “Arginine biosynthesis,” while AAA was linked to “Phenylalanine metabolism” and “Valine, leucine, and isoleucine biosynthesis.” No horizontal pleiotropy was detected, and results were robust. Conclusions Identified metabolites and pathways may serve as potential biomarkers and therapeutic targets for the clinical assessment and prevention of TAA and AAA.