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

摘要：肾脏和终末期肾脏疾病(ESRD)中的种族不平等已经有了很好的文献记载。 并独立于较低的社会经济地位(例如，收入、教育)、较低的获得护理的机会或其他 常规风险因素。研究已经确定了许多肾脏疾病的遗传风险因素，尤其是 非洲人后裔中出现的APOL1变异体。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增加的一个重要且在很大程度上未被探索的决定因素 与白人相比，黑人患肾脏疾病的风险更大。事实上，邻里环境可以相互作用 与遗传易感性导致肾脏疾病的不平等。澄清邻里关系的作用是 重要的是，社区既不是随机的，也不是自然发生的。他们通过发展和改变 政策，因此是可以干预的。尽管有证据表明 对于社区肾脏疾病的主要危险因素和决定因素，缺乏经验性研究 研究社区在肾脏疾病本身中的作用，特别是在终末期肾病前期。这个 这一领域研究面临的主要挑战是：(A)缺乏训练有素的研究人员 肾脏疾病的科学、病理生理学和遗传科学；和(B)数据集的匮乏 包含高质量的邻里关系、临床和遗传措施。 为了实现我的长期职业目标，成为一名成功的、独立的研究员，澄清社会 种族CKD不平等的原因以及遗传和生物医学机制，我将解决目前的科学 拟议的培训和研究带来的挑战，分别是：(A)补充我在 生物科学和社会科学方面的广泛培训，在 肾脏疾病的病理生理学和遗传学；以及(B)制定最先进的邻里措施，以 现有的高质量数据集重复了肾功能和损害的临床测量。 我将谈到三个职业目标： 1.接受正规的肾脏生理学和病理生理学培训。 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 肾脏疾病。 3.通过R01提交文件，迈出独立的第一步。 我的培训将包括指导和与遗传学和病理生理学方面的领先专家合作。 关于CKD不平等、遗传流行病学、统计学/人口遗传学和肾脏的正式课程 生理学/病理生理学，以及关于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，多种族研究 动脉粥样硬化和肾病综合征研究网络)之间的互动关系 四个邻域的多项措施(种族居住隔离、社会环境、建筑 环境、卫生保健资源)和遗传风险(APOL1和β-珠蛋白HBb基因型别，调整 遗传祖先)，如下所示： 目标1：将邻里关系的四个领域的最新措施与人口代表性联系起来， 包含肾脏疾病标志物的流行病学和临床队列数据集。 目标2：通过调整，检查社区环境和肾脏健康之间的纵向联系 遗传血统和APOL1基因。 目标3：考察邻里环境对载脂蛋白1之间纵向联系的调节作用 高危基因状态与肾脏健康。 完成此培训和创建数据集后，我将阐明最紧密的邻域特征 与肾脏结果直接相关，也通过它们与遗传风险基因座的相互作用联系在一起。这项研究将设置 为研究肾脏疾病的邻里特征和不平等现象奠定了坚实的基础。不仅会 这项研究阐明了邻居和遗传风险在这些不平等中的相互依赖作用，但它将 找出与肾脏疾病有关的、易于改变的关键邻里特征 在不同种族之间。 UM是我培训和研究的理想场所，因为它是国际公认的领先研究 大力支持跨学科科学的机构。我加入了两所社会学院的教职 研究(ISR)是因为它致力于跨学科研究，而肾脏病是因为它的 致力于澄清导致肾脏疾病的社会暴露。在ISR内部，肾脏病 和公共卫生学院，我将接受严格的培训，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.