Stroke is the third leading cause of death in industrialized countries and the leading cause of disability in adults. Epidemiological and twins studies strongly support an inherited component to stroke risk. The broad long-term objective of this application is to clarify the molecular basis for inherited ischemic stroke risk. The application focuses on thrombosis genes because of overwhelming evidence for the etiologic relevance of thrombosis in acute ischemic stroke that comes from clinical prevention and treatment trials and emergent angiography studies.
The specific aims of this application are: (1) to collect DNA and create immortalized cell lines from patients with recent ischemic stroke and from healthy control subjects and (2) to test for associations between ischemic stroke and candidate thrombosis genes. The candidate genes to be tested are the beta fibrinogen gene and genes that code for components of 3 platelet glycoprotein receptors GPIIb/IIIa, GPIb, and GPla. These genes were selected based on previous studies demonstrating associations between variations in these genes and ischemic stroke, either overall or in subgroup analyses. Four hundred and fifty [450] patients with recent CTIMR-confirmed ischemic stroke will be recruited from inpatient services at 5 US clinical centers over 3 years. Four hundred and fifty [450] controls will be enrolled concurrently. Matching criteria will be age, sex, and race (African-American versus non-African-American). The prospective design of this application permits rigorous exploration of whether there is heterogeneity in genetic risk factors among common ischemic stroke subtypes that are defined clinically. Patients will have dual subtyping by certified study neurologists using standardized classification systems: the Trial of ORG 10172 Acute Stroke Treatment (TOAST) system and the Oxfordshire Community Stroke Project system. This application has been designed to permit valid pooled analyses with SWISS, an ongoing affected sibling pair study supported by the NINDS (ROI NS39987). The application and SWISS share the same definitions for the present and absence of phenotype and key enrollment criteria.
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