Objective To evaluate the causal relationships between circulating cytokines (CCs) and aortic aneurysm (AA) and aortic dissection (AD) collectively known as AAD using two-sample Mendelian randomization (MR) analysis.

Methods A meta-analysis based on genome-wide association studies (GWASs) involving 8, 293 individuals was conducted to obtain genetic variations associated with CCs as instrumental variables. The AADrelated GWAS statistics data were obtained from the Finnish database as the outcome, with all samples originating from European populations. The control group for the outcome data comprised 349, 539 individuals, with 881 cases of AD and 7, 395 AA. Among these, thoracic aortic aneurysms (TAA) accounted for 3, 510 cases, and abdominal aortic aneurysms (AAA) for 3, 548 cases. The study utilized inverse variance weighting as the primary analytical method, complemented by weighted median method, MR-Egger regression, MR pleiotropy residual sum and outlier test, and corresponding sensitivity analyses. Finally, reverse MR analysis was employed to assess reverse causal relationships.

Results In the forward MR analysis following Bonferroni correction, it was observed that elevated levels of TNF-related apoptosis-inducing ligand (TRAIL) were identified as a risk factor for AD (OR=1.25, P=0.0002), while the other positive results (0.0002 < P < 0.05) indicated potential causal relationships as follows: TRAIL with AA (OR=1.06) and TAA (OR=1.09); monocyte chemoattractant protein-1 (MCP-1) with AA (OR=1.13), TAA (OR=1.18), and AD (OR=1.46); IFN-γ with AA (OR=0.82) and TAA (OR=0.75); interleukin-16 (IL-16) (OR=0.9), interferon-gamma-induced monocyte chemoattractant protein (MIG) (OR=1.14), and macrophage inflammatory protein-1 beta (MIP-1β) (OR=0.96) with TAA. In the reverse MR analysis, potential causal relationships were identified between AAD and some CCs, including a positive correlation between AA and MCP-1; a positive correlation between TAA and eosinophil activating chemotactic factor (EOTAXIN) and a negative correlation with IL-13; and positive correlations between AD and beta nerve growth factor (β-NGF), IL- 1β, IL-8, and tumor necrosis factor-alpha (TNF-a). Sensitivity analysis results indicated no heterogeneity or pleiotropy in the causal effects between CCs and AAD.

Conclusion The levels of TRAIL and MCP-1 in circulation are causally related to the risk of developing AD, AA, and TAA, indicating a potential target for early screening of patients with AD, AA, and TAA as well as for the development of therapeutic drugs.