Cerebal Hemmorage Risk in Heredotary Hempprrahagic Telangiectasia

我们建议利用多中心国际BVMC HHT招募网络和BVMC HHT数据库，在下一个资金周期中，表征患有BAVM的HHT患者及其亚组的颅内出血(ICH)风险。为此，我们建议扩大HHT BAVM患者的队列，建立在我们建立的多中心HHT BAVM数据库的基础上，这是世界上最大的此类队列。在目标1中，通过将队列规模扩大一倍并延长自然病史随访，我们将提高HHT BAVM患者以及患者亚组的脑出血发生率的精确度，并将这些估计纳入临床决策的相关范围。在目标2中，我们建议基于第一个BVMC周期的初步证据，研究HHT和BAVM表型的遗传修饰因素。我们证明了ALK1变异IVS3-35A和GT；G与HHT疾病的严重程度(存在任何器官动静脉畸形)相关，特别是在ENG突变的患者中。因此，我们假设了二次打击或反式杂合性假说，即除了致病突变外，TGFbeta/BMP9信号通路功能的进一步降低还会加剧HHT的表型。为了验证这一假设，我们将评估通路基因中的常见变异与(1)HHT患者的“任何AVM”和(2)BAVM风险的关联，并探索它们与ICH风险和其他HHT严重表型的关联。我们将利用最初的BVMC HHT队列(n=800,200 BAVM)进行发现，并利用新的第二周期HHT队列800进行复制。目的3是一个探索性的目标，我们计划研究BAVM和ICH的管壁炎症，使用管壁成像和组织回顾炎性细胞和介质。项目3的参与者将通过12个HHTT英才中心以及患者支持组织HHTFI(HHTFI)招募。HHT调查组将继续与HHTFI以及DMCC密切合作，利用已建立的DMCC基于网络的门户、数据收集和管理协议。BVMC HHT项目将继续为临床神经血管学界研究HHT中的BAVM提供急需和宝贵的资源。

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.