Common Variants in Interleukin-1-Beta Gene Are Associated with Intracranial Hemorrhage and Susceptibility to Brain Arteriovenous Malformation

Background: Polymorphisms in the proinflammatory cytokine interleukin (IL)-1 beta gene have been associated with systemic atherogenesis, thrombosis and rupture. The aim of this study was to investigate associations between single nucleotide polymorphisms (SNPs) in IL-1 beta and intracranial hemorrhage (ICH) in the natural course of brain arteriovenous malformation (BAVM) patients. Method: Two IL-1 beta promoter SNPs (-511C -> T, -31T -> C) and 1 synonymous coding SNP in exon 5 at + 3953C -> T (Phe) were genotyped in 410 BAVM patients. We performed a survival analysis of time to subsequent ICH, censoring cases at first treatment, death or last follow-up. A Cox regression analysis was performed to obtain hazard ratios (HRs) for genotypes adjusted for age, sex, Caucasian race/ethnicity and hemorrhagic presentation. Results: Subjects with the -31 CC genotype (HR = 2.7; 95% CI 1.1-6.6; p = 0.029) or the -511 TT genotype (HR = 2.6; 95% CI 1.1-6.5; p = 0.039) had a greater risk of subsequent ICH compared with reference genotypes, adjusting for covariates. The + 3953C -> T SNP was not significantly associated with an increased ICH risk (p = 0.22). The IL-1 beta promoter polymorphisms were also associated with BAVM susceptibility among a subset of 235 BAVM cases and 255 healthy controls of Caucasian race/ethnicity (p < 0.001). Conclusion: IL-1 beta promoter polymorphisms were associated with an increased risk of ICH in BAVM clinical course and with BAVM susceptibility. These results suggest that inflammatory pathways, including the IL-1 beta cytokine, may play an important role in ICH. Copyright (C) 2008 S. Karger AG, Basel