Genetic influences on clinical outcome in brain arteriovenous malformations

描述(申请人提供)：脑动静脉畸形(AVM)是年轻人颅内出血(ICH)的重要原因。动静脉动静脉畸形的病因和发病机制尚不清楚。治疗是侵入性的，对于未破裂的动静脉动静脉畸形的临床处理仍然存在争议。我们小组之前的工作已经在临床过程中发现了与AVM和新的脑出血相关的基因。然而，新的脑出血的决定因素可能不同于那些影响出血事件或治疗相关损伤的不良预后的因素。识别脑损伤后功能结局的遗传预测因子可能有助于更好地管理AVM患者的风险预测，并促进对脑出血性疾病的了解。这项研究计划的总体目标是更好地了解脑动静脉畸形的发病机制和对不良结果的潜在遗传易感性。具体地说，我的目标是使用候选基因方法，确定1)脑出血造成的脑损伤或2)脑AVM患者接受侵入性治疗后，用改进的Rankin量表衡量的结果的遗传预测因子。第三，我们将解决人口分层的方法问题，即按种族/族裔进行遗传混杂，这是在多族裔人口中进行的所有遗传关联研究的潜在问题。这些目标将在加州大学旧金山分校脑动静脉畸形研究项目和健康对照的现有和新的动静脉动静脉畸形病例队列中仔细描述并积极跟踪完成。候选人是一名受过博士培训的心血管遗传流行病学家，致力于以患者为中心的中风研究，重点是脑部出血性疾病。这项申请提出了一个全面的五年计划，将候选人发展成为一名独立的中风研究人员，包括临床培训，如在中风诊所和手术室观察中风患者的治疗，统计方法和生物信息学的高级培训，以及高通量基因分型技术的实验室实践培训。候选人的长期目标是通过结合流行病学、生物统计学、遗传学和神经学的技能，成为中风遗传学研究的独立领导者。加州大学旧金山分校以病人为导向的导师职业发展奖和先进的培训环境将确保候选人在这些努力中取得成功。

DESCRIPTION (provided by applicant): Brain arteriovenous malformations (AVMs) are an important cause of intracranial hemorrhage (ICH) in young adults. The etiology and pathogenesis of AVMs are not well understood. Treatment is invasive and controversy remains over the clinical management of unruptured AVMs. Previous work by our group has identified genes associated with AVM and new ICH in the clinical course. However, the determinants of new ICH may differ from those that influence poor outcome from a hemorrhagic event or treatment-related injury. Identification of genetic predictors of functional outcome after brain injury may help facilitate risk prediction for better management of AVM patients and advance understanding of hemorrhagic diseases of the brain. The overall goal of this research proposal is to better understand the pathogenesis of brain AVMs and the underlying genetic susceptibility to adverse outcomes. Specifically, my goals are to identify genetic predictors of outcome measured by the modified Rankin scale after 1) brain injury from ICH or 2) invasive treatment in brain AVM patients, using a candidate gene approach. Thirdly, we will address methodological issues of population stratification, i.e., genetic confounding by race/ethnicity, which is a potential problem for all genetic association studies conducted in multiethnic populations. These objectives will be completed in a carefully characterized, actively followed cohort of existing and new AVM cases from the UCSF Brain AVM Study Project and healthy controls. The candidate is a PhD trained cardiovascular genetic epidemiologist dedicated to a career in patient-oriented stroke research focusing on hemorrhagic diseases of the brain. This application proposes a comprehensive 5-year plan to develop the candidate into an independent stroke researcher, including clinical training, such as attendance in stroke clinics and operating room to observe stroke patient treatment, advanced training in statistical methods and bioinformatics, and hands on laboratory training in high throughput genotyping techniques. The candidate's long-term objective is to become an independent leader in stroke genetics research by combining skills in epidemiology, biostatistics, genetics, and neurology. The Mentored Patient-Oriented Career Development Award and the advanced training milieu at UCSF will ensure the candidate's success in these endeavors.