Margaret T. Hicken, Ph.D. - US grants

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 ?-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.

ABSTRACT Racial inequalities in healthy aging have been well-documented. Compared to White Americans, Black Americans experience illness and death at early ages and show steeper age-related declines in health. Our neighborhoods, as the site of where we live, learn, play, and pray, may serve as a powerful source of these racial inequalities. Racial residential segregation (which is the sorting of different racial groups into different neighborhoods through historical and current discriminatory policies and practices) has resulted in a racially unequal American neighborhood landscape. Neighborhoods with mostly Black residents experience more poverty, civic and commercial disinvestment, and more exposure to environmental hazards compared to neighborhoods with mostly White residents. While more researchers are documenting the role of neighborhoods in health inequalities, we may actually be underestimating the true impact of neighborhood context, because we often focus on specific health outcomes, such as cardiovascular disease or diabetes. However, there are likely shared biological mechanisms within the body that drive many of these diseases ? and one such mechanism may be changes to our genomic structure, called epigenomics. While our genes do not change, the environment can have an impact on whether our genes are actually ?expressed?. We will determine whether the accumulation of adulthood lived experience in racially-segregated neighborhoods is related to epigenomic patterns called DNA methylation. We will also specifically determine whether the accumulation of adulthood exposure to neighborhood industrial air pollution and disadvantage together are related to these patterns of DNA methylation. Finally, we will determine whether the DNA methylation patterns we see are related to racial inequalities in healthy aging. We hypothesize that racially-segregation Black neighborhoods, with their greater levels of industrial air pollution and social disadvantage, will be related to the types of patterns in DNA methylation that have been shown to be related to chronic diseases in molecular studies. In fact, we further hypothesize that these patterns in DNA methylation will be related to racial inequalities in cognitive function and the number of chronic diseases one has had. Clarifying the role of neighborhood context in racial inequalities in healthy aging is critical, as neighborhoods are not naturally- occurring. They develop and change through policies and are amenable to intervention. Identifying the role of DNA methylation that likely underlies many chronic diseases, will clarify the importance of neighborhoods and point to potential effective interventions.

Black-White inequities in healthy aging are well-known with Black adults experiencing greater risk of developing and earlier onset of chronic conditions such as cardiovascular disease (CVD), hypertension, and diabetes compared to White adults. Neighborhood context has emerged as a potentially powerful determinant of racial inequities in aging-related health conditions, including cognitive decline, and may be a key intervention site. Neighborhoods include both social and environmental exposures important for healthy aging. Evidence indicates stark racial inequities in exposure to segregated, under-resourced but over-surveilled and polluted neighborhoods. Pollution and aspects of social adversity are often correlated and may operate cumulatively to result in racial health inequities. Importantly, however, these chemical (i.e. pollution) and non-chemical (i.e., social adversity) stressors may act synergistically, whereby exposure to social adversity can heighten vulnerability to the deleterious health impact of even low levels of pollution. Yet, the environmental and social science literatures ? even the environmental and social epidemiology literatures ? are largely separate. There is a pressing need to integrate the study of these exposures given their likely cumulative and synergistic effects on racial health inequities in order to direct effective interventions and policies. In addition to the gaps in our knowledge about the combined impact of chemical and non-chemical stressors on racial inequities in healthy aging, there is a need to focus on outcomes that may serve as biological pathways to numerous diseases. Research on either pollution or social adversity has tended to focus on specific health outcomes. Focus on a single disease may underestimate the overall health impact of these racially unequal exposures. It is critical to clarify the shared biological mechanisms that underlie numerous chronic diseases to understand the full impact of pollution and social adversity on racial health inequities. A growing literature points to the importance of epigenetic factors, particularly DNA methylation, linking socioenvironmental context to health. Indeed, it may be that epigenetic processes are an important mechanism through which inequities in both air pollution and social adversity are embodied. Our objective is to identify underlying DNA methylation mechanisms linking neighborhood segregation and ambient and industrial air pollution and social adversity to measures of healthy aging. Clarifying the role of neighborhood in racial health inequities is critical, as neighborhoods are amenable to intervention. Identifying the role of DNA methylation patterns reflecting racial segregation, including chemical and non-chemical stressors, can point to specific disease etiologies and causal mechanisms effective interventions to eliminate racial inequities in healthy aging.