: Despite increasing recognition of the efficacy of anti-coagulation for prevention of Thromboembolism, its use remains limited by the risk of Intracerebral Hemorrhage (ICH). Improved understanding of the biological basis of ICH offers the possibility that genetic tests might identify patients at particularly high risk prior to initiation of therapy. Building on the Principal Investigator's studies of genetic risk factors for ICH, we propose a pharmacogenetic investigation of warfarin-related ICH. This study will be based at five major stroke referral centers: Massachusetts General Hospital; Columbia-Presbyterian Medical Center; Boston Medical Center; Cornell Medical Center; and the University of Michigan Health System. Consecutive ICH patients and matched control subjects will be analyzed for polymorphisms in apolipoprotein-E, the fibrin cross-linking enzyme factor XIII, the cytokine-transforming growth factor-131, and its receptor-associated protein Endoglin, each a gene with suggested links to ICH. A case-control analysis will be used to determine whether the candidate genotypes are associated with the occurrence of warfarin-related ICH. Based on preliminary data suggesting possible genetic determinants of ICH outcome, we will also analyze the ICH cohort, prospectively, for the effects of genotype on hematoma volume, hematoma expansion, patient mortality, and functional status. Parallel analyses will be conducted among patients with Warfarin-related ICH, and no-treatment ICH to determine whether any identified risk factors are specific to hemorrhages that occur with Warfarin. We anticipate that additional candidate genes will continue to emerge during the course of the proposed studies, given rapid growth in our knowledge of both the human genome and the molecular basis of coagulation and vascular pathology. This proposal is thus likely to form the foundation of a powerful, open-ended search for a panel of genetic tests to determine an individual's risk for Warfarin-related ICH.
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