Single nucleotide polymorphisms associated with sporadic brain arteriovenous malformations: where do we stand?

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 174G4C (odds ratio = 1.97; 95% confidence interval: 1.15–3.38) and the tumour necrosis factor a 238G4A (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 -35A4G (odds ratio = 2.42; 95% confidence interval: 1.54–3.8) gene polymorphism and disease susceptibility.