Abstract
Thoracic aortic aneurysm (TAA) is associated with changes in the levels of metabolites; however, the exact causal relationships remain unclear. Identifying this complex relationship may provide new insights into the pathogenesis of TAA. We used genome-wide association studies to investigate the relationship between metabolites and TAA in this study. A total of 1400 serum metabolites were investigated for their potential causal effects on the risk of TAA. We performed bidirectional and 2-sample Mendelian randomization (MR) analysis using 5 MR tests: MR-Egger, weighted mode, weighted median, inverse variance weighted (IVW), and simple mode. We also performed sensitivity analysis to verify our findings, including heterogeneity analysis using IVW and MR-Egger tests and pleiotropy analysis using the MR-Egger test. Multiple metabolites were identified as having a causal effect on the risk of TAA, particularly those related to lipid metabolites; the top 2 risk factors identified using the IVW test were 3-carboxy-4-methyl-5-pentyl-2-furanpropionate (P = .019) and 5alpha-androstan-3alpha,17alpha-diol (P = .021), whereas the 2 top protective factors were 1-stearoyl-2-docosahexaenoyl-gpc (P = .023) and 1-oleoyl-2-docosahexaenoyl-GPC (P = .005). Sensitivity analysis verified the lack of heterogeneity (P = .499, .584, .232, and .624, respectively; IVW test) or pleiotropy (P = .621, .483, .598, and .916, respectively; Egger test). Our study provides new evidence of a causal relationship between metabolites and the risk of TAA, thus providing new insights into the pathogenesis of this disease. These findings suggest a promising approach for metabolite-based therapeutic interventions.