Project Abstract: Stroke is the second leading cause of death worldwide. In the United States, stroke is the fifth leading cause of death and a leading cause of serious, long-term disability. One quarter of strokes are recurrences. African Americans have nearly two-fold greater risk of suffering a stroke, 60% higher risk of recurrent stroke, and are twice as likely to die from stroke compared to European Americans. Recurrent strokes are more often fatal and result in even greater disability than first strokes in survivors. To date, few studies have focused on the interplay of social and structural determinants of health, epigenetic factors and genetic variants in stroke and recurrent stroke risk. To address this knowledge gap, we will generate and evaluate DNA methylation data while leveraging genome-wide single nucleotide polymorphism (SNP) genotype data and phenotypic data from individuals with stroke, recurrent stroke, or no stroke from the REasons for Geographic and Racial Differences in Stroke (REGARDS) study as well as participants from the Vitamin Intervention for Stroke Prevention (VISP) clinical trial. Expanding our prior genetic and epigenetics studies, we hypothesize that we will identify DNA methylation sites and genetic markers influencing susceptibility for recurrent stroke and identify key social and structural determinants of health that mediate stroke and stroke recurrence risk. We will test our hypothesis by performing epigenome-wide association analyses for stroke and recurrent stroke risk including mediation analyses considering comorbidities, environmental factors, and biomarkers, generating genetic and epigenetic risk scores, and performing convergent -omics approaches. This represents a powerful and innovative technique to identify genetic and epigenetic contributors to stroke and recurrent stroke risk and may allow improved personalization of risk assessment and targeted prevention of strokes as we work to eliminate stroke disparities.