Polymorphisms of Inflammatory Cytokine Genes and Risk for Intracranial Aneurysm: A Systematic Review and Meta-Analysis

Abstract

Purpose: Inflammatory cytokines are thought to be involved in the pathogenesis of intracranial aneurysm (IA), although results among studies in the literature are inconsistent. This article sought to review studies on the associations among polymorphisms in inflammatory cytokine genes and IA risk and to provide recommendations for future research. Materials and Methods: A systematic search of PubMed, Embase, and Web of Science was conducted up to August 4, 2019. The associations between polymorphisms of inflammatory cytokine genes and IA risk were estimated by pooled odds ratios (ORs) and 95% confidence intervals (CIs). Subgroup analyses were performed according to race. Qualitative systematic review was conducted for variants that were studied in only one study. All analyses were performed using STATA 12.0. Results: 13 studies investigating the associations between polymorphisms in five inflammatory cytokine genes (TNF-α, IL-1α, IL-1β, IL6, and IL-12B) and IA were reviewed. Combined results showed that the A allele of TNF-α rs1800629 polymorphism has a protective effect against IA (dominant model: OR=0.65, 95% CI=0.47-0.89, p=0.007). No associations were identified between polymorphisms in IL-1α rs1800587, IL-1β rs16944, IL6 rs1800795 and rs1800796, or IL-12B rs3212227 and IA risk. Conclusion: This review demonstrated an association between TNF-α rs1800629 polymorphism and IA in Caucasians, illustrating the potentially important role of genes involved in inflammation in IA.

Circulating inflammatory biomarkers and risk of intracranial aneurysm: a Mendelian randomization study

“…Our result was supported by a previous MR study which showed sIL6R and CRP levels were not associated with IA [ 8 ]. Our finding was partially contradictory to a meta-analysis, which found no evidence of IL-1α, IL-1β, IL-6, and IL-12β against IA, but identified significant association of TNF-α polymorphism with IA [ 51 ]. Still, current epidemiological and experimental evidence for the role of inflammatory biomarkers in the formation and progression of IA remained insufficient, and thereby required future research to unveil the mystery.…”

Association of Interleukin-6 Signaling and C-Reactive Protein With Intracranial Aneurysm: A Mendelian Randomization and Genetic Correlation Study

“…A meta-analysis showed that two IL6 promoter polymorphisms (−174G/C and −572G/C) were associated with IA (Zheng et al, 2013). However, another recently published meta-analysis failed to confirm this association (Hu et al, 2020). Furthermore, 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.…”

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

“…Electronic databases including PubMed, Embase, and Web of Science were used for articles that had been published up to August 2022. The following key words were determined by referring to previous articles and used in “and” combinations [ 16 ] : “intracranial aneurysm(s)” or “cerebral aneurysm(s)” or “subarachnoid hemorrhage”, “inflammation” or “inflammatory cytokine” or “interleukin” or “tumor necrosis factor” or “high mobility group box 1” or “genetic” ( Fig. 1 and Supplementary Table 1 ).…”

“…Clinical information (e.g., authors, year, ethnicity, age, gender, and sample size) and genetic information (e.g., gene, SNP, and allele frequency) were collected. The quality of enrolled studies was evaluated using the Newcastle-Ottawa quality assessment scale [ 16 ]. The fixed-effect model assumes that one true effect size underlies all studies in the meta-analysis having a less heterogeneity between studies.…”

“…Several inflammation-related gene loci have been reported to be associated with IA susceptibility using single nucleotide polymorphism (SNP) or genetic linkage analysis. Among the various inflammation-related genetic variants, a previous meta-analysis revealed that the rs1800629 polymorphisms (TNF-α) was closely associated with IA in Caucasians [ 16 ]. Also, rs1800796 (IL-6) showed opposite effects with respect to the formation of IA between Caucasian and Chinese populations, although there was no statistical significance.…”