Abstract

Background and objectiveEvidence suggests that interleukin-6 (IL6) signaling is causally associated with aortic aneurysm independently of the effect of C-reactive protein (CRP). We aimed to explore the genetic overlap and associations between inflammation (IL6 signaling and CRP) and intracranial aneurysm (IA) risk.MethodsTwo-sample Mendelian randomization (MR) methods were used to assess the causal effects of soluble IL6 receptor (sIL6R) (n = 21,758) and CRP (n = 204,402) levels on IA (7,495 cases and 71,934 controls) risk using genome-wide association study summary data of European individuals. Cross-trait linkage disequilibrium score regression was used to estimate the genetic correlations of CRP (n = 400,094) with IA.ResultsMR analyses showed that circulating sIL6R and CRP levels were not associated with the risk of IA. The odds ratios based on the inverse variance-weighted method were 0.986 (0.950–1.023, p = 0.45) and 0.957 (0.846–1.084, p = 0.49) for sIL6R and CRP, respectively. MR analyses using data of ruptured and unruptured IA each showed no association. Linkage disequilibrium score regression showed that the genetic correlation between CRP and IA was 0.16 (SE = 0.04, p = 0.0003). The genetic correlation diminished after conditioning IA on blood pressure (0.07 ± 0.05, p = 0.16), smoking (0.02 ± 0.05, p = 0.65), or blood pressure plus smoking (−0.03 ± 0.05, p = 0.53).ConclusionUsing associated genetic variants as instrument variables, two-sample MR analyses showed no evidence that circulating sIL6R and CRP levels were associated with IA risk. Although a positive genetic correlation was found between CRP levels and IA risk, it was mainly driven by the shared genetic background of blood pressure and smoking with both CRP and IA.

Highlights

  • Intracranial aneurysm (IA) is characterized by balloon-shaped dilatation of the vascular wall of intracranial arteries, occurring predominantly in the circle of Willis

  • Mendelian randomization analysis using genome-wide association study (GWAS) summary data of ruptured and unruptured IA separately showed no evidence of association (Figure 2)

  • Mendelian randomization (MR) analysis using GWAS summary data of ruptured and unruptured IA separately showed no evidence of association

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Summary

Introduction

Intracranial aneurysm (IA) is characterized by balloon-shaped dilatation of the vascular wall of intracranial arteries, occurring predominantly in the circle of Willis. A meta-analysis showed that two IL6 promoter polymorphisms (−174G/C and −572G/C) were associated with IA (Zheng et al, 2013). A case-control study showed that levels of C-reactive protein (CRP), which is a well-established downstream molecule of IL6 signaling, were higher in patients with fusiform IA than controls (Mota Telles et al, 2020).With the increasing availability of summary data from genome-wide association studies (GWASs), new methods such as two-sample Mendelian randomization (MR) and linkage disequilibrium score (LDSC) regression have been widely used to determine the relationship between traits. Evidence suggests that interleukin-6 (IL6) signaling is causally associated with aortic aneurysm independently of the effect of C-reactive protein (CRP). We aimed to explore the genetic overlap and associations between inflammation (IL6 signaling and CRP) and intracranial aneurysm (IA) risk

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