Causal association between circulating inflammatory cytokines and intracranial aneurysm and subarachnoid hemorrhage

Abstract

Background and purpose: The causal association between inflammatory cytokines and the development of intracranial aneurysm (IA), unruptured IA (uIA) and subarachnoid hemorrhage (SAH) lacks clarity.

Methods: The summary-level datasets for inflammatory cytokines were extracted from a genome-wide association study of the Finnish Cardiovascular Risk in Young Adults Study and the FINRISK survey. The summary statistics datasets related to IA, uIA and SAH were obtained from the genome-wide association study meta-analysis of the International Stroke Genetics Consortium and FinnGen Consortium. The primary method employed for analysis was inverse variance weighting (false discovery rate), supplemented by sensitivity analyses to address pleiotropy and enhance robustness.

Results: In the International Stroke Genetics Consortium, 10, six and eight inflammatory cytokines exhibited a causal association with IA, uIA and SAH, respectively (false discovery rate, p < 0.05). In FinnGen datasets, macrophage Inflammatory Protein-1 Alpha (MIP_1A), MIP_1A and interferon γ-induced protein 10 (IP_10) were verified for IA, uIA and SAH, respectively. In the reverse Mendelian randomization analysis, the common cytokines altered by uIA and SAH were vascular endothelial growth factor (VEGF), MIP_1A, IL_9, IL_10 and IL_17, respectively. The meta-analysis results show that MIP_1A and IP_10 could be associated with the decreased risk of IA, and MIP_1A and IP_10 were associated with the decreased risk of uIA and SAH, respectively. Notably, the levels of VEGF, MIP_1A, IL_9, IL_10 and TNF_A were increased with uIA. Comprehensive heterogeneity and pleiotropy analyses confirmed the robustness of these results.

Conclusion: Our study unveils a bidirectional association between inflammatory cytokines and IA, uIA and SAH. Further investigations are essential to validate their relationship and elucidate the underlying mechanisms.

Keywords: Mendelian randomization; causal association; inflammatory cytokines; intracranial aneurysm; subarachnoid hemorrhage.

FIGURE 1

Study design of the bidirectional two‐sample MR for the causal association between genetically predicted inflammatory cytokines and IA, uIA and SAH. IA, intracranial aneurysm; ISGC, International Stroke Genetics Consortium; IV, instrumental variable; MR, Mendelian randomization; SAH, subarachnoid hemorrhage; SNP, single nucleotide polymorphism; uIA, unruptured intracranial aneurysm.

FIGURE 2

Forest plot of results from a meta‐analysis of MR results and replicate MR results. IA, intracranial aneurysm; MR, Mendelian randomization; SAH, subarachnoid hemorrhage; uIA, unruptured intracranial aneurysm.

FIGURE 3

Forest plot of results from a meta‐analysis of reverse MR results and replicate reverse MR results. MR, Mendelian randomization; SAH, subarachnoid hemorrhage; uIA, unruptured intracranial aneurysm.