Circulating Inflammatory Biomarkers and Risk of Intracranial Aneurysm: A Mendelian Randomization Study

Abstract

Abstract Background Intracranial aneurysm (IA) accounts for a substantial source of non-traumatic subarachnoid hemorrhage, with inflammation postulated as a potential factor in its pathogenesis. The present study aims at evaluating the association between circulating inflammatory cytokines and risk of IA under a bidirectional two-sample Mendelian randomization (MR) design. Methods For primary analysis, summary statistics of inflammatory regulators was obtained from a genome-wide association study (GWAS) comprising 8,293 Finnish participants. Summary data of IA was extracted from a GWAS which comprised 7,495 cases and 71,934 controls in European descent. For targeted analysis, summary statistics were extracted from two proteomic studies, which recruit 3,301 and 5,368 European participants, respectively. Summary data of IA were acquired from FinnGen study with 5,342 cases and 342,673 controls. We employed inverse variance weighted (IVW) method as main approach, with sensitivity analyses using weighted median, MR-Egger, and MR-PRESSO methods. Reverse MR analyses were conducted to minimize bias from reverse causality. Results No causation of cytokines with IA was identified in both primary and targeted analysis after Bonferroni correction. In primary analysis, vascular endothelial growth factor (VEGF) and fibroblast growth factor basic (bFGF) levels were suggestively associated with IA [(VEGF→IA: odds ratio (OR) = 1.11, 95% confidence interval (95% CI) = 1.02–1.20, P = 0.01; bFGF→IA: OR = 0.68, 95% CI = 0.48–0.96, P = 0.03]. Statistical significance failed to replicate in targeted analysis. Instead, suggestive protective effects for aneurysmal subarachnoid hemorrhage (aSAH) were identified in FGF-9 (FGF-9→aSAH: OR = 0.74, 95% CI = 0.62–0.89, P = 0.001) and FGF-16 (FGF-16→aSAH: OR = 0.84, 95% CI = 0.72–0.97, P = 0.017). Furthermore, reverse analyses identified suggestive effect of IA and its subtypes on IL-10, RANTES, MIF, GRO-alpha, FGF-16, and FGF-19. Result remained robust after applying sensitivity tests. Conclusions Our study provided novel insights into the potential protective role of FGF-9 and FGF-16 in aSAH. Future studies are in need to evaluate the temporal dynamics of cytokines in conjunction with IA.