Cerebal Hemmorage Risk in Heredotary Hempprrahagic Telangiectasia

我们建议在下一个资助周期中利用多中心国际BVMC HHT招募网络和BVMC HHT数据库来表征伴有bavm和亚组的HHT患者颅内出血（ICH）的风险。为此，我们建议在我们已建立的世界上最大的多中心HHT BAVM数据库的基础上，扩大HHT BAVM患者的队列。通过将队列规模扩大一倍并延长自然史随访，在Aim 1中，我们将提高HHT BAVM患者总体以及患者亚组中脑出血发生率的准确性，并将这些估计值纳入临床决策的相关范围。在目标2中，我们建议基于第一次BVMC周期的初步证据，研究HHT和BAVM表型的遗传修饰因子。我们证明ALK1变异IVS3-35A>G与HHT疾病严重程度（任何器官avm的存在）相关，特别是在ENG突变患者中。因此，我们假设二次打击或反杂合假说，该假说指出，除了致病突变外，TGFBeta/BMP9信号通路功能的进一步降低会加剧HHT表型。为了验证这一假设，我们将评估途径基因的常见变异与HHT患者(1)“任何avm”和(2)BAVM风险的关系，并探索与ICH风险和其他HHT严重表型的关系。我们将使用初始BVMC HHT队列（n= 800,200 BAVM）进行发现，并使用新的第二周期HHT队列800进行复制。Aim 3是一个探索性目标，我们计划利用血管壁成像和炎症细胞和介质的组织检查来研究bavm和ICH的血管壁炎症。项目3的参与者将通过12个HHT卓越中心以及HHT国际基金会（HHTFI）患者支持组织招募。HHT调查小组将继续与HHTFI以及DMCC密切合作，利用已建立的DMCC网络门户网站、数据收集和管理协议。BVMC HHT项目将继续为临床神经血管界研究HHT中的bavm提供急需的宝贵资源。

We propose to leverage the multicenter international BVMC HHT recruitment network and the BVMC HHT database, in the next funding cycle, to characterize the risk of intracranial hemorrhage (ICH) in HHT patients with BAVMs and subgroups. To do so, we propose to expand the cohort of HHT BAVM patients, building on our established multicenter HHT BAVM database, the largest such cohort in the world. By doubling the cohort size and extending natural history follow-up, in Aim 1 we will increase precision of ICH rates in HHT BAVM patients overall, as well as subgroups of patients, and bring these estimates into a relevant range for clinical decision making. In Aim 2, we propose to investigate genetic modifiers of HHT and BAVM phenotypes, building on preliminary evidence from the first BVMC cycle. We demonstrated that the ALK1 variant IVS3-35A>G is associated with HHT disease severity (presence of any organ AVMs), particularly in patients with an ENG mutation. We therefore postulate a second-hit or trans-heterozygosity hypothesis, which states that in addition to the disease-causing mutation, further reduction of function in the TGFBeta/BMP9 signaling pathway exacerbates HHT phenotypes. To test this hypothesis, we will evaluate common variants in pathway genes for their association with (1) "any AVMs" and (2) BAVM risk in HHT patients and explore associations with ICH risk and other HHT severity phenotypes. We will utilize the initial BVMC HHT cohort (n=800, 200 BAVM) for discovery and the new second-cycle HHT cohort of 800 for replication. Aim 3 is an exploratory aim, in which we plan to study vessel wall inflammation in BAVMs and ICH, using vessel wall imaging and tissue review for inflammatory cells and mediators. Project 3 participants will be recruited through 12 HHT Centers of Excellence, as well as the Patient Support Organization, HHT Foundation International (HHTFI). The HHT investigator group will continue to work closely with the HHTFI, as well as with the DMCC, leveraging the established DMCC web-based portal, data collection and management protocols in place. The BVMC HHT Project will continue to provide a much-needed and valuable resource for the clinical neurovascular community for the study of BAVMs in HHT.