PROJECT SUMMARY/ABSTRACT – Research Project Leader: Stacy Brown, MD Association of Genetic Determinants of Diabetes with Cerebrovascular Disease in Multi-Ancestral Hawai'ian Populations Global increases in prevalent type 2 diabetes (T2D) and cerebrovascular disease means that health systems need to meet increasing demand for preventive and therapeutic interventions. In addition to traditional public health efforts, innovative health systems are developing and beginning to offer precision medicine strategies based on genomic information. However, genetically derived instruments for evaluating T2D and cerebrovascular risk are based on genetic studies performed in populations of predominantly European ancestry. For populations underrepresented in these derivation studies, the clinical yield of precision medicine strategies is lower. In the Pacific Islands, epidemiologic research has already identified high rates of diabetes, obesity, hypertension, and hyperlipidemia among Native Hawaiians and Pacific Islanders (NHPI), relative to other residential populations. Strokes occur at younger ages and with higher mortality and morbidity in NHPI individuals. Particularly in populations like NHPI who are already vulnerable to health and health system inequities, ensuring representation in translational and clinical genetics research is paramount to efforts to reduce population health disparities in the future. Our proposed work aims to tackle the knowledge gaps described by comprehensively studying the relationship between the genetic underpinnings of T2D and Our central hypothesis is that there is variation in the frequency of important disease-associated polymorphisms across ancestral groups, and in particular in NHPI compared to previously studied populations. To test this hypothesis, we will leverage the diverse backgrounds of participants in the Multi-Ethnic Cohort (MEC) Study and global genotyping coverage of the Population Architecture using Genomics and Epidemiology (PAGE) exomechip array. We will (1) comprehensively evaluate the genetic architecture of diabetes and stroke risk in a population of Native Hawaiian cerebrovascular disease in NHPI. ancestry; (2) generate and systematically evaluate polygenic risk scores for diabetes and other stroke risk factors in the Native Hawaiian cohort and other ethnic groups in the MEC and a predominantly European database, UK Biobank; (3) explore the associations between genetically determined diabetes and age at first . By identifying differences in the genetic contributions to cerebrovascular disease in presently underrepresented populations, our study will generate results to contextualize prospective research aimed to responsibly increase inclusivity of diverse populations in genetic studies. presentation of major cerebrovascular events