This NIH Revision application for Physical Frailty in Urban African Americans (PFUAA;AG10436) responds to PAR-08-065. It requests 3 years of funding to enable additional data collection on a representative well-characterized cohort of African Americans living in St. Louis, MO, (the African American Health project, or AAH). Data to be collected relate to potential interactions between genetic factors and depression in mediating coronary artery disease (CAD) risk in AAH using single SNP/haplotype association analyses. CAD is the leading cause of cardiovascular morbidity and mortality in the U.S. Nationally, African Americans have higher morbidity-mortality rates from CAD than whites, and particularly so in Missouri and in the city of St. Louis. Depression is also common and has multiple adverse associations with CAD. These relationships have been understudied in population-based samples and especially in African Americans. As frailty and disability are associated with both atherosclerotic disease and depressive symptoms, better understanding of the genetic reasons for the adverse CAD-depression associations is crucial to the AAH project. Prior data indicate that these conditions are common in AAH, with 3-year period prevalences of 42% for cardiovascular diseases and 31% for clinically relevant levels of depressive symptoms. Despite the well-known CAD-depression adverse associations, the precise genetic factors and molecular mechanisms mediating them remain largely unknown. The overarching hypothesis of this project is that depression contributes to the development and sequelae of CAD through common gene-gene (GXG) and/or gene-environment (GXE) interactions. To examine this hypothesis, this NIH Revision project will enroll 450 AAH subjects to pursue three specific aims: SA1. Identify the prevalence of CAD and depression phenotypes in a population-based sample of community-dwelling 57-75 year old African Americans. SA2. Examine the relationships between the CAD and depression phenotypes in this population, highlighting the modulating role of selected genes in the serotonin and inflammatory pathways. SA3. Discover potential gene-depression interactions with significant contribution to the development of CAD in African Americans. We have assembled an outstanding multidisciplinary group with all the required expertise to conduct this research, including epidemiology (aging, depression, cardiovascular, and genetic), cardiac imaging, CAD and depression phenotyping, cardiovascular disease mutation analysis, and (crucially) the development and use of novel statistical methods to study genetic polymorphisms for translational studies of cardiovascular disease. We plan to follow this project with a larger grant application to recruit 1050 additional subjects and perform genome wide analyses to address these important issues in even greater depth. This research has the potential to identify excellent targets for pharmacological and non-pharmacological approaches to preventing, ameliorating, or reversing either or both of these important conditions. PUBLIC HEALTH RELEVANCE: Coronary artery disease is a leading cause of death and health problems in the U.S. and has a particularly strong impact on African Americans. The presence of depression increases the frequency of coronary artery disease and all its complications in both blacks and whites. The purpose of this research is to examine the relationship between coronary artery disease and depression in an ongoing study of African Americans living in St. Louis, Missouri with an emphasis on understanding how genetic factors interact with depression symptoms to exert such a strong negative impact on coronary artery disease.