We provide the first report of an association between polymorphic variants in the IL-1β gene with both ICH risk in the natural course of BAVM patients and BAVM susceptibility. Several lines of evidence support our findings. First, all 3 SNPs have previously been implicated in various cerebrovascular phenotypes, including ischemic injury [3
], stroke [9
] and aneurysmal rupture [10
]. For example, the TT genotype of the IL-1β −511C→T polymorphism was significantly associated with an increased risk of subarachnoid hemorrhage [10
] and small vessel disease stroke [32
] in a Polish population, but with a decreased risk of ischemic stroke in an Italian population [9
]. Second, animal studies have shown that IL-1β expression levels are significantly upregulated after intracerebral hemorrhage [33
]. Third, all 3 polymorphisms are located in known functional regions of the IL-1β gene (the promoter and an exon), and several studies have demonstrated a genotype-phenotype association. The T allele of the −511 promoter SNP is correlated with enhanced IL-1β production in vivo[34
], and the −31 promoter SNP is located in a TATA box transcription initiation site [28
]. The +3953C→T (Phe) variant has been shown to influence in vitro IL-1β production in some [35
] but not in all studies [37
]. Haplotypes containing both −511T and −31C alleles have been shown to have increased transcriptional activity in vitro [38
]. Thus, the increased ICH risk in IL-1β high-risk genotype carriers may be due to increased local or peripheral inflammation influencing AVM disease progression.
The IL-1β gene located on chromosome 2q14 is approximately 7 kb long with 7 exons. However, it sits in an IL-1 cytokine cluster spanning approximately 430 kb, containing genes for IL-1α, IL-1β and IL-1 receptor antagonist. Therefore, the association we observed with IL-1β variants could possibly be due to linkage disequilibrium (LD) with variants in these related IL-1 genes or additional variants in the IL-1β gene. As expected, analyses of both IL-1β promoter SNPs yielded similar findings due to the strong LD. Thus, we cannot distinguish whether 1 of the 2 promoter SNPs, or another SNP in the same LD block, is responsible for the observed associations with BAVM susceptibility and ICH.
An increasing number of reports suggest a role of inflammatory signaling in BAVM pathogenesis. Activin-like kinase 1, a transforming growth factor-β superfamily member, is mutated in hereditary hemorrhagic telangiectasia; a common activin-like kinase 1 polymorphism is also strongly associated with sporadic BAVM [39
]. The GG genotype of the IL-6 174G→C promoter polymorphism was associated with clinical presentation of ICH in BAVM patients [41
] and with highest IL-6 expression levels in BAVM tissue [8
]; IL-6 levels correlated strongly with IL-1β mRNA levels [8
]. Compared with control brain (structurally normal cortex removed during temporal lobectomy), BAVM tissue had an order of magnitude higher expression of the leukocyte marker myeloperoxidase, which highly correlated and colocalized with matrix metalloprotease 9 and IL-6 expression [7
]. Finally, a promoter polymorphism in the tumor necrosis factor-α (−238G→A) gene was associated with new hemorrhage in the natural course of a sample of 280 BAVM cases; the presence of the A allele increases the risk of ICH [12
Together, these results suggest that inflammatory mechanisms are involved in BAVM susceptibility and progression and warrant replication and further investigation into the precise mechanism of how proinflammatory pathways are involved. A better understanding of BAVM pathogenesis is needed to prevent ICH and potentially help develop novel therapeutics for patient management.