sIL-6R impact on aortic aneurysm: Genetic evidence from FinnGen and GWAS

The causal relationship between soluble interleukin-6 receptor (sIL-6R) and the risk of aortic aneurysm (AA) is unclear. This study used a two-sample Mendelian randomization (MR) approach, utilizing FinnGen and GWAS data, to investigate the potential causal link between sIL-6R and AA risk.

A two-phase study was conducted to comprehensively assess potential causal relationships. In the discovery phase, we applied five analytical methods: inverse variance weighting (IVW), weighted mode, MR-Egger regression, and weighted median regression. Leave-one-out analysis was conducted to ensure the robustness of our results. For external validation, we used two independent FinnGen datasets to confirm the initial findings. To address potential pleiotropy and strengthen our conclusions, we also employed Bayesian weighted Mendelian randomization.

In the discovery phase, genetically predicted higher levels of sIL-6R were significantly associated with a reduced risk of AA (odds ratio [OR] = 0.9429, 95 % confidence interval [CI], 0.9190-0.9674; P = 7.0 × 10^-6). External validations reinforced this association, with the first validation yielding an OR of 0.9316 (95 % CI: 0.8938-0.9710, P = 0.0008) and the second validation an OR of 0.9340 (95 % CI: 0.8970-0.9725, P = 0.0009). In contrast, initial positive findings for the IL-6 signaling pathway were not confirmed in external validations, with no significant associations in either validation (ORs 1.5584 and 1.5204, P > 0.05).

Our MR study confirms a causal link between higher genetically predicted sIL-6R levels and reduced AA risk. Further research is needed to understand the underlying mechanisms and develop prevention strategies.