Causal relationships between the circulating levels of cytokines and risk of aortic aneurysm and aortic dissection:a bidirectional two-sample Mendelian randomization study
Objective:To evaluate the causal relationships between circulating cytokines(CCs)and aortic aneu-rysm(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 AAD-related GWAS statistics data were obtained from the Finnish database as the outcome,with all samples originat-ing 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 ab-dominal 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 ob-served 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 relation-ships 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);inter-leukin-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 plei-otropy 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.
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