Genetically Predicted Vascular Proteins and Risk of Intracranial Aneurysms: A Mendelian Randomization Study

The relationship between vascular proteins (VPs) and intracranial aneurysms (IAs) has not been fully elucidated. We used Mendelian randomization (MR) analysis to explore the effect of VPs on IAs. Dataset of aneurysmal subarachnoid hemorrhage (aSAH) [5140 cases and 71,934 controls] and unruptured intracranial aneurysm (uIA) [2070 cases and 71,934 controls] were obtained from individuals of European ancestry. Univariate MR was used to explore the associations between 90 VPs and IAs. Then, we performed multivariate MR (MVMR) to further investigate the identified VP-to-IA estimates. Two-sample MR showed that TNFSF14 was inversely associated with aSAH (odds ratio [OR] = 0.831, 95% CI: 0.713-0.969, p = 0.018). IL-16 (OR = 1.218, 95% CI: 1.032-1.438, p = 0.020) and AgRP (OR = 1.394, 95% CI: 1.048-1.855, p = 0.023) were positively associated with aSAH. HBEGF (OR = 0.642, 95% CI: 0.461-0.894, p = 0.009), MCP-1 (OR = 1.537, 95% CI: 1.007-2.344, p = 0.046), and CX3CL1 (OR = 0.762, 95% CI: 0.581-0.999, 0.049 < p < 0.050) were associated with uIA risk. The MVMR showed that the TNFSF14-to-aSAH estimate remained statistically significant after adjustment for past tobacco smoking, alcohol consumption, systolic blood pressure and body mass index. Our study indicated that low serum TNFSF14 levels might be a potential risk factor for IA rupture. Five VPs (HBEGF, MCP-1, IL-6, CX3CL1, and AgRP) are associated with the risk of IAs (both uIA and aSAH).