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

项目总结/摘要 本NIH F31-多样性申请的目的是为PI Alana Jones获得支持， 在她的MD/PhD学位培训中指导研究和职业发展活动，这将加强她的能力。 成为一名独立的科学家。该项目的目标是发展遗传学技能， 流行病学和生物信息学，这将使她能够识别遗传和表观遗传风险标志物，以及 在非裔美国人中开发慢性肾病（CKD）的多基因和甲基化风险评分（目的1 和2），他们的发病率和患病率不成比例地高。此外，她将测试 这些评分在预测与CKD相关的不良结局，特别是终末期肾病中的效用 疾病（ESRD）（目标3）。这些方法包括全基因组和表观基因组关联研究， 多变量回归建模，以及风险评分校准和判别（例如，C统计量）。主 本研究的目的是确定CKD的个体标志物，并将其整合为预测指标 算法CKD影响了14%的美国人口，并正在稳步上升，成为全球死亡的主要原因。 由于约90%的CKD患者在晚期之前无症状，因此早期风险分层可能对 预防临床后遗症，如终末期肾病。核心假设是多基因和甲基化评分 可能能够预测生物学CKD风险及其相关结果，作为遗传和表观遗传变异 有助于CKD的遗传性。她研究的长期目标是了解遗传性 研究人员正在研究影响健康差异的各种因素，并开发指导治疗战略的临床工具。 PI的拟议培训计划由其项目导师Marguerite（Ryan）Irvin博士赞助。 培训计划中包括帮助PI在以下主要领域发展的经验：1）严格 CKD领域的研究，包括熟悉现有的CKD流行病学文献， 差异、科学完整性和负责任的研究行为的原则，以及遗传学的应用 CKD结局的风险预测; 2）遗传流行病学，包括方法学、结果解释，以及 对已发表的多基因和甲基化风险评分进行严格评估;以及3）职业和专业 发展，包括学习手稿和赠款写作，期刊评审，数据展示， 将研究成果转化为临床应用。培训计划的总体目标是提供PI 作为一个独立的物理学家，科学家的职业生涯的坚实基础，与领导一个 一个合作研究小组，弥合健康差距决定因素研究与 实施卫生政策，以改善心血管健康结果。

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.