Genetic and Epigenetic Risk Scores for Chronic Kidney Disease in African Americans

项目总结/文摘

PROJECT SUMMARY/ABSTRACT The purpose of this NIH F31-Diversity application is to obtain support for the PI, Alana Jones, for mentored research and career development activities within her MD/PhD degree training that will strengthen her potential to become an independent physician-scientist. The project goal is to develop skills in genetic epidemiology and bioinformatics that will allow her to identify genetic and epigenetic risk markers, as well as develop polygenic and methylation risk scores for chronic kidney disease (CKD) in African Americans (Aims 1 and 2), who experience disproportionately higher incidence and prevalence of disease. Additionally, she will test the utility of these scores in predicting adverse outcomes associated with CKD, particularly end-stage renal disease (ESRD) (Aim 3). These methods include genome-wide and epigenome-wide association studies, multivariate regression modeling, and risk score calibration and discrimination (e.g., C statistic). The primary objective of this research proposal is to identify individual markers for CKD and consolidate them into a prediction algorithm. CKD impacts 14% of the US population and is steadily rising as a major cause of mortality globally. As CKD is asymptomatic in ~90% of people until advanced stages, early risk stratification may be critical to preventing clinical sequelae, such as ESRD. The central hypothesis is that polygenic and methylation scores may be able to predict biological CKD risk and its associated outcomes, as both genetic and epigenetic variants contribute to the heritability of CKD. The long-term objective of her research is to understand how heritable factors influence health disparities and to develop clinical tools that guide treatment strategies. The proposed training plan for the PI is sponsored by her project mentor, Dr. Marguerite (Ryan) Irvin. Included in the training plan are experiences to help the PI develop in the following major areas: 1) rigorous research in the CKD field, including developing familiarity with the existing literature on CKD epidemiology and disparities, principles of scientific integrity and responsible conduct of research, and the application of genetic risk prediction for CKD outcomes; 2) genetic epidemiology, including methodology, interpretation of results, and critical evaluation of published polygenic and methylation risk scores; and 3) career and professional development, including learning skills in manuscript and grant writing, journal review, data presentation, and translation of research findings to clinical application. The overall goal of the training plan is to provide the PI with a solid foundation for a career as an independent physician-scientist, with the ultimate goal of leading a collaborative research team that bridges the gap between research on determinants of health disparities and the implementation of health policy in order to improve cardiovascular health outcomes.