Human brain arteriovenous malformation (BAVM) tissue contains increased levels of vascular endothelial growth factor A (VEGFA). We carried out a case-control study to determine whether polymorphisms in the VEGFA gene are associated with sporadic BAVM. Nine selected VEGFA single-nucleotide polymorphisms (SNP) were genotyped in 319 patients with BAVM and 333 controls from a Chinese population using the MassARRAY genotyping system. We found four single variants in the VEGFA gene (rs1547651, rs2010963, rs833069 and rs3025010), with one haplotype, ACT, possibly associated with the risk of developing BAVM.
"The patients who presented the AG/GG genotypes of the rs833069 showed a higher risk of brain arteriovenous malformation compared with the AA genotype. A significantly protective effect was instead associated with the AT/TT genotypes of rs1547651 compared with AA genotype, the GG/GC genotype of rs2010963 compared with CC genotype, and TT/TC genotypes of rs3025010 compared with CC genotype (Chen et al., 2011). "
[Show abstract][Hide abstract] ABSTRACT: Brain arteriovenous malformations are characterized by a tangle of abnormal vessels directly shunting blood from the arterial to venous circulation. They are known to occur either sporadically or in the context of well-defined genetic disorders. Haemorrhage represents the most severe clinical manifestation, whereas other common symptoms include headache, seizures and neurological deficits. Although sporadic forms do not recognize a specific genetic cause, in recent years, it has been hypothesized that genes involved in angiogenesis and inflammation or coding for proteins, such as fibronectins, laminins and integrins, may play a role in the pathophysiology of brain arteriovenous malformations. More recently, a new trend of genetic studies has investigated the association between sporadic arteriovenous malformations and single nucleotide polymorphisms, single base variations between genomes within members of a biological species or between paired chromosomes in an individual, which may determine the susceptibility to develop complex diseases and influence their natural history. Several polymorphisms in two different families of genes have been associated with disease susceptibly and increased haemorrhagic risk. These genes are mainly involved in the inflammatory cascade and in the regulation of angiogenesis. However, most of the investigated polymorphisms have been selected on the basis of candidate genes because of their potential functional role in the pathogenesis of brain arteriovenous malformations or in other cerebrovascular diseases. Only one hypothesis-free genome-wide association study in a small number of patients has been performed so far, but it was unable to identify significant associations between brain arteriovenous malformations and specific genetic loci. In this article, we review and analyse the polymorphisms investigated to date in association with sporadic brain arteriovenous malformations in the medical literature. We discuss the biological, pathophysiological and clinical implications of these studies, with particular attention to the prediction of haemorrhagic risk and the possibility of building genetic profiles capable of defining the architectural features of the malformations and predict their evolution and natural history. We also present a joint analysis of the risk estimates found by the studies in literature that have evaluated the association between single nucleotide polymorphisms and brain arteriovenous malformation susceptibility and risk of bleeding. This analysis shows a statistically significant association between the interleukin 6 -174G>C (odds ratio = 1.97; 95% confidence interval: 1.15-3.38) and the tumour necrosis factor α -238G>A (odds ratio = 2.19; 95% confidence interval: 1.25-3.83) gene polymorphisms and risk of intracranial haemorrhage and between the activin-like kinase 1 (also known as ACVRL1) intervening sequence 3 -35A>G (odds ratio = 2.42; 95% confidence interval: 1.54-3.8) gene polymorphism and disease susceptibility.
[Show abstract][Hide abstract] ABSTRACT: To evaluate the influence of the vascular endothelial growth factor A (VEGFA) polymorphisms on risk of presentation with intracerebral hemorrhage (ICH).
Nine selected VEGFA single-nucleotide polymorphisms (SNPs) were genotyped in 311 patients with brain arteriovenous malformations (BAVM) in a Chinese population. Associations between individual SNPs/haplotypes and the hemorrhage risk of BAVMs were evaluated using logistic regression analysis.
In the single-locus analysis, rs1547651 was associated with increased risk of ICH (adjusted OR=2.11, 95% CI=1.01-4.42 compared with the AA genotype). In particular, an increased risk for ICH was associated with this variant in female patients (adjusted OR=3.21, and 95% CI=0.99-10.36). Haplotype-based analyses revealed that haplotype 'GC' in block 1 and haplotype 'ACC' in block 2 were associated with a 30%-38% reduction in the risk of ICH in patients with BAVMs compared to the most common haplotype (P(sim)=0.033 and P(sim)=0.005, respectively). The protective effect of haplotype 'ACC' in block 2 was more evident in male patients and subjects with BAVMs of a size ≥3 cm (adjusted OR=0.57, 95% CI=0.34-0.97 and adjusted OR=0.57, 95% CI=0.31-0.86, respectively).
The results suggest that VEGFA gene variants may contribute to ICH risk of BAVM.
[Show abstract][Hide abstract] ABSTRACT: Background:
In genome-wide association studies (GWAS) five putative risk loci are associated with intracranial aneurysm. As brain arteriovenous malformations (AVM) and intracranial aneurysms are both intracranial vascular diseases and AVMs often have associated aneurysms, we investigated whether these loci are also associated with sporadic brain AVM.
We included 506 patients (168 Dutch, 338 American) and 1548 controls, all Caucasians. Controls had been recruited as part of previous GWAS. Dutch patients were genotyped by KASPar assay and US patients by Affymetrix SNP 6.0 array. Associations in each cohort were tested by univariable logistic regression modelling, with subgroup analysis in 205 American cases with aneurysm data. Meta-analysis was performed by a Mantel-Haenszel fixed-effect method.
In the Dutch cohort none of the single nucleotide polymorphisms (SNPs) were associated with AVMs. In the American cohort, genotyped SNPs near SOX-17 (OR 0.74; 95% CI 0.56-0.98), RBBP8 (OR 0.76; 95% CI 0.62-0.94) and an imputed SNP near CDKN2B-AS1 (OR 0.79; 95% CI 0.64-0.98) were significantly associated with AVM. The association with SNPs near SOX-17 and CDKN2B-AS1 but not RBBP8 were strongest in patients with AVM with associated aneurysms. In the meta-analysis we found no significant associations between allele frequencies and AVM occurrence, but rs9298506, near SOX-17 approached statistical significance (OR 0.77; 95% CI 0.57-1.03, p=0.08).
Our meta-analysis of two Caucasian cohorts did not show an association between five aneurysm-associated loci and sporadic brain AVM. Possible involvement of SOX-17 and RBBP8, genes involved in cell cycle progression, deserves further investigation.
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