Genetic influences on clinical outcome in brain arteriovenous malformations

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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.