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

摘要：肾脏和终末期肾病（ESRD）的种族不平等已得到充分记录 并且独立于较低的社会经济地位（例如，收入，教育），获得护理的机会较少，或其他 传统的风险因素。研究已经确定了许多肾脏疾病的遗传风险因素，特别是 APOL 1变异发生在非洲人后裔中。然而，这些遗传因素主要是增加 易感性，需要疾病发展的其他因素。 越来越多的研究表明，社区对健康和健康不平等的重要性。 不平等的邻里环境可能是一个重要的和很大程度上未探索的决定因素增加 与白人相比，黑人经历的肾脏疾病风险。事实上，邻里环境可能会相互作用， 遗传易感性导致肾脏疾病的不平等。明确邻里的作用是 重要的是邻居既不是随机的也不是自然发生的。它们通过 政策，因此可以进行干预。尽管有证据表明， 社区的主要危险因素和肾脏疾病的决定因素，缺乏经验的 研究社区在肾脏疾病本身中的作用，特别是在ESRD前阶段。的 这一领域的研究面临的主要挑战是：（a）缺乏受过社会和经济两方面培训的熟练研究人员， 科学和肾脏疾病的病理生理学和遗传科学;以及（B）缺乏 包含高质量的邻域以及临床和遗传测量。 为了实现我的长期职业目标，成为一名成功的独立研究人员， 种族CKD不平等的原因和遗传和生物医学机制，我将解决目前的科学 通过拟议的培训和研究，分别应对挑战，办法是：（a）补充我在 生物科学和社会科学的广泛培训， 肾脏疾病的病理生理学和遗传学;以及（B）创建最先进的邻近测量， 现有数据集具有高质量的重复临床肾功能和损害测量。 我将实现三个职业目标： 1.获得肾脏生理学和病理生理学的正式培训。 2.发展与种族不平等有关的遗传流行病学和人口遗传学方面的专门知识， 肾病 3.通过R 01提交向独立迈出第一步。 我的培训将包括指导和合作，与领先的专家在遗传学和病理生理学 CKD不平等，遗传流行病学，统计/群体遗传学和肾脏疾病的正式课程 生理学/病理生理学，以及有关遗传学实质性主题的多次会议和研讨会， 种族、CKD和职业发展。 通过我的研究项目，我将使用三个队列（健康和退休研究， 动脉粥样硬化和肾病综合征研究网络），以检查 四个邻里领域（种族居住隔离，社会环境，建成 环境和卫生保健资源）和遗传风险（APOL 1和β-珠蛋白HBB基因型，调整 遗传祖先），如下： 目标1：将邻里环境的四个领域的最新测量与人口代表性相关联， 流行病学和包含肾病标志物的临床队列数据集。 目的2：检查邻里环境与肾脏健康之间的纵向关联，并进行调整 遗传祖先和APOL 1基因型。 目的3：检查邻近环境对APOL 1之间纵向关联的修饰作用。 高风险基因型状态和肾脏健康。 通过这种训练和数据集的创建，我将阐明与我们的目标最紧密相关的邻域特征。 直接或通过与遗传风险基因座的相互作用与肾脏结局相关。这项研究将使 为研究肾脏疾病的邻域特征和不平等奠定了坚实的基础。不仅会 这项研究阐明了邻里和遗传风险对这些不平等的相互依赖的作用，但它将 确定与肾脏疾病相关的关键邻域特征，这些特征易于改变， 种族群体之间。 UM是我的培训和研究的理想场所，因为它是国际公认的领先研究 这是一个非常支持跨学科科学的机构。我加入了社会研究所和 研究（ISR），因为它致力于跨学科研究，和肾脏病，因为它 致力于澄清导致肾脏疾病的社会暴露。在ISR内，肾脏科 部门和公共卫生学院，我将获得严格的培训和发展坚实的合作 致力于澄清CKD种族不平等的社会和遗传原因。

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.