Department of Neurosurgery, Catholic University School of Medicine, Rome, Italy.
Brain. 2013 Feb;136(Pt 2):665-81. doi: 10.1093/brain/aws180. Epub 2012 Sep 13.
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.
脑动静脉畸形的特征是异常血管的纠结，这些血管直接将血液从动脉分流到静脉循环。已知它们要么是散发性的，要么是在明确的遗传疾病的背景下发生的。出血是最严重的临床表现，而其他常见症状包括头痛、癫痫发作和神经功能缺损。虽然散发性形式没有特定的遗传原因，但近年来，有人假设参与血管生成和炎症的基因或编码纤维连接蛋白、层粘连蛋白和整合素等蛋白质的基因可能在脑动静脉畸形的病理生理学中发挥作用。最近，一种新的遗传研究趋势调查了散发性动静脉畸形与单核苷酸多态性之间的关联，单核苷酸多态性是指在生物物种的成员之间或个体的配对染色体之间基因组内的单个碱基变化，这些变化可能决定了患复杂疾病的易感性，并影响其自然病史。两个不同基因家族的几个多态性与疾病易感性和出血风险增加有关。这些基因主要参与炎症级联和血管生成的调节。然而，大多数被研究的多态性是根据候选基因选择的，因为它们在脑动静脉畸形或其他脑血管疾病的发病机制中具有潜在的功能作用。迄今为止，只进行了一项针对少数患者的基于假说的全基因组关联研究，但未能确定脑动静脉畸形与特定遗传位点之间的显著关联。在本文中，我们回顾和分析了迄今为止在医学文献中与散发性脑动静脉畸形相关的多态性。我们讨论了这些研究的生物学、病理生理学和临床意义，特别关注出血风险的预测以及构建能够定义畸形结构特征并预测其演变和自然病史的遗传特征的可能性。我们还介绍了对评估单核苷酸多态性与脑动静脉畸形易感性和出血风险关联的文献研究中发现的风险估计值的联合分析。该分析显示白细胞介素 6-174G>C（比值比=1.97；95%置信区间：1.15-3.38）和肿瘤坏死因子α-238G>A（比值比=2.19；95%置信区间：1.25-3.83）基因多态性与颅内出血风险之间以及激活素样激酶 1（也称为 ACVRL1）内含子 3-35A>G（比值比=2.42；95%置信区间：1.54-3.8）基因多态性与疾病易感性之间存在统计学显著关联。
