The Interactive Roles of Neighborhood Characteristics and Genetic Risk in Racial Inequalities in CKD

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ABSTRACT: Racial inequalities in kidney and end stage renal diseases (ESRD) have been well-documented and are independent of lower socioeconomic status (e.g., income, education), lower access to care, or other conventional risk factors. Research has identified numerous genetic risk factors of renal disease, particularly the APOL1 variants occurring in persons of African descent. However, these genetic factors primarily increase susceptibility, requiring other factors for the development of disease. A growing body of research indicates the importance of neighborhoods for health and health inequalities. Unequal neighborhood contexts may be an important and largely unexplored determinant of the increased kidney disease risk experienced by Blacks compared to Whites. In fact, neighborhood context may interact with genetic susceptibility to result in kidney disease inequalities. Clarifying the role of neighborhood is important as neighborhoods are neither random nor naturally-occurring. They develop and change through policies and are thus amenable to intervention. Despite the evidence indicating the importance of neighborhoods for the major risk factors and determinants of kidney disease, there is a dearth of empirical research on the role of neighborhoods in relation to kidney disease itself, particularly at pre-ESRD stages. The primary challenges to research in this area are: (a) the lack of skilled researchers with training in both social science and the pathophysiology and genetic science of kidney disease; and (b) the paucity of datasets that contain high quality neighborhood and clinical and genetic measures. To reach my long-term career goal to become a successful, independent researcher who clarifies the social causes and genetic and biomedical mechanisms of racial CKD inequalities, I will address the current scientific challenges through the proposed training and research, respectively by: (a) complementing my early work in the biological sciences and extensive training in the social sciences with extensive training in the pathophysiology and genetics of kidney disease; and (b) creating state-of-the-art neighborhood measures to existing datasets with high quality repeat clinical measures of renal function and damage. I will address three career goals: 1. To obtain formal training in renal physiology and pathophysiology. 2. To develop expertise in genetic epidemiology and population genetics pertaining to racial inequalities in kidney disease. 3. To take the first step toward independence through an R01 submission. My training will include mentorship and collaboration with leading experts in the genetics and pathophysiology of CKD inequalities, formal coursework in genetic epidemiology, statistical/population genetics, and renal physiology/pathophysiology, and multiple conferences and workshops on the substantive topics of genetics, race, and CKD and on professional development. Through my research project, I will use three cohorts (Health and Retirement Study, Multi-Ethnic Study of Atherosclerosis, and Nephrotic Syndrome Study Network) to examine the interactive associations between multiple measures of four neighborhood domains (racial residential segregation, social environment, built environment, and health care resources) and genetic risk (APOL1 and β-globin HBB genotypes, adjusting for genetic ancestry), as follows: Aim 1: Link state-of-the-art measures of four domains of neighborhood context to population-representative, epidemiological, and clinical cohort datasets containing markers of kidney disease. Aim 2: Examine longitudinal associations between neighborhood context and renal health, with adjustment for genetic ancestry and APOL1 genotype. Aim 3: Examine the modifying role of neighborhood context on longitudinal associations between APOL1 high-risk genotype status and renal health. With this training and dataset creation, I will then clarify the neighborhood characteristics that are most tightly linked to renal outcomes both directly and through their interactions with genetic risk loci. This research will set a solid foundation for research on neighborhood characteristics and inequalities in kidney disease. Not only will this research clarify the interdependent roles of neighborhood and genetic risk on these inequalities, but it will identify key neighborhood characteristics, which are amenable to change, related to kidney disease within and between racial groups. UM is the ideal venue for my training and research as it is internationally recognized as a leading research institution that strongly supports interdisciplinary science. I joined the faculty both at the Institute for Social Research (ISR) because of its commitment to interdisciplinary research, and Nephrology because of its commitment to clarifying the social exposures that contribute to kidney disease. Within ISR, the Nephrology Division, and School of Public Health, I will acquire rigorous training and develop solid collaborations devoted to the clarification of the social and genetic causes of racial inequalities in CKD.