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，以表征具有BAVM和亚组的HHT患者的颅内出血（ICH）风险。为此，我们建议在我们建立的多中心HHT BAVM数据库（世界上最大的此类队列）的基础上扩展HHT BAVM患者队列。通过将队列规模加倍并延长自然史随访，在目标1中，我们将提高HHT BAVM患者总体以及患者亚组的ICH发生率的精确度，并将这些估计值纳入临床决策的相关范围。在目标2中，我们建议研究HHT和BAVM表型的遗传修饰剂，建立在第一个BVMC周期的初步证据基础上。我们证明ALK 1变体IVS 3 - 35 A>G与HHT疾病严重程度（存在任何器官AVM）相关，特别是在具有ENG突变的患者中。因此，我们提出了二次打击或反式杂合性假说，即除了致病突变外，TGF β/BMP 9信号通路功能的进一步降低会加剧HHT表型。为了检验这一假设，我们将评价通路基因的常见变异与HHT患者中（1）“任何AVM”和（2）BAVM风险的相关性，并探索与ICH风险和其他HHT严重程度表型的相关性。我们将利用初始的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是一个探索性目的，我们计划使用血管壁成像和组织检查来研究BAVM和ICH中的血管壁炎症，以检测炎症细胞和介质。项目3的参与者将通过12个HHT卓越中心以及患者支持组织HHT国际基金会（HHTFI）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、数据收集和管理协议。BVMC HHT项目将继续为临床神经血管社区提供急需的宝贵资源，以研究HHT中的BAVM。

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.