Genetic influences on clinical outcome in brain arteriovenous malformations

描述（由申请方提供）：脑动静脉畸形（AVM）是年轻成人颅内出血（ICH）的重要原因。AVM的病因和发病机制尚不清楚。治疗是侵入性的，未破裂AVM的临床管理仍存在争议。我们小组以前的工作已经确定了与AVM和临床过程中新发ICH相关的基因。然而，新发ICH的决定因素可能与出血性事件或治疗相关损伤影响不良结局的决定因素不同。识别脑损伤后功能结局的遗传预测因子可能有助于促进风险预测，以更好地管理AVM患者，并促进对脑出血性疾病的理解。本研究提案的总体目标是更好地了解脑AVM的发病机制和潜在的遗传易感性不良结局。具体而言，我的目标是使用候选基因方法，在1）ICH脑损伤或2）脑AVM患者的侵入性治疗后，通过改良兰金量表确定结局的遗传预测因子。第三，我们将讨论人口分层的方法问题，即，种族/民族的遗传混杂，这是在多民族人群中进行的所有遗传关联研究的潜在问题。这些目标将在UCSF脑AVM研究项目现有和新发AVM病例和健康对照的仔细表征、积极随访队列中完成。该候选人是一名经过博士培训的心血管遗传流行病学家，致力于以患者为导向的中风研究，重点是脑出血性疾病。该申请提出了一个全面的5年计划，将候选人培养成为独立的卒中研究人员，包括临床培训，例如在卒中诊所和手术室观察卒中患者治疗，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。指导病人为导向的职业发展奖和在UCSF先进的培训环境将确保候选人在这些努力的成功。

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.