Updated Trans-Ethnic Meta-Analysis of Associations between Inflammation-Related Genes and Intracranial Aneurysm

Abstract

Objective: We performed an expanded multi-ethnic meta-analysis to identify associations between inflammation-related loci with intracranial aneurysm (IA) susceptibility. This meta-analysis possesses increased statistical power as it is based on the most data ever evaluated.

Methods: We searched and reviewed relevant literature through electronic search engines up to August 2022. Overall estimates were calculated under the fixed- or random-effect models using pooled odds ratio (OR) and 95% confidence intervals (CIs). Subgroup analyses were performed according to ethnicity.

Results: Our meta-analysis enrolled 15 studies and involved 3070 patients and 5528 controls including European, Asian, Hispanic, and mixed ethnic populations. Of 17 inflammation-related variants, the rs1800796 locus (interleukin [IL]-6) showed the most significant genome-wide association with IA in East-Asian populations, including 1276 IA patients and 1322 controls (OR, 0.65; 95% CI, 0.56-0.75; p=3.24×10-9) under a fixed-effect model. However, this association was not observed in the European population (OR, 1.09; 95% CI, 0.80-1.47; p=0.5929). Three other variants, rs16944 (IL-1β), rs2195940 (IL-12B), and rs1800629 (tumor necrosis factor-α) showed a statistically nominal association with IA in both the overall, as well as East-Asian populations (0.01<p<0.05).

Conclusion: Our updated meta-analysis with increased statistical power highlights that rs1800796 which maps on the IL-6 gene is associated with IA, and in particular confers a protective effect against occurrence of IA in the East-Asian population.

Keywords: Inflammation mediators; Interleukin-6; Intracranial aneurysm; Meta-analysis.

Fig. 1.

PRISMA flow diagram of candidate study selection from reviewing previous genetic or genome-wide association studies focused on inflammation-related genes in intracranial aneurysm. PRISMA : Preferred Reporting Items for Systematic Reviews and Meta-Analyses.

Fig. 2.

A : Funnel plot with pseudo 95% confidence limits for rs1800796 (interleukin [IL]-6) in the overall meta-analysis. X-axis indicates the natural logarithm of odds ratio (ln[OR]). Y-axis indicates standard error of ln(OR). Solid and short-dash lines indicate the overall effect and 95% confidence intervals, respectively. B : Forest plots of rs1800796 in the inverse variance meta-analysis excluding study heterogeneity. The diamonds indicate estimates of pooled OR from the fixed-effect (first diamond) and random-effect (second diamond) models. L95 : lower 95% confidence interval, U95 : upper 95% confidence interval.