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

项目摘要/摘要 此NIH F31-分集应用程序的目的是获得对PI Alana Jones的支持 在她的医学/博士学位培训中指导研究和职业发展活动，这将增强她的能力 有可能成为一名独立的内科医生兼科学家。该项目的目标是培养遗传方面的技能。 流行病学和生物信息学，使她能够识别遗传和表观遗传风险标记，以及 制定非裔美国人慢性肾脏疾病(CKD)的多基因和甲基化风险评分(目标1 和2)，他们经历了不成比例的高发病率和流行率。此外，她还将测试 这些评分在预测慢性肾脏病，特别是终末期肾脏病相关不良结局中的作用 疾病(ESRD)(目标3)。这些方法包括基因组范围和表观基因组范围的关联研究， 多变量回归建模，以及风险分数校准和判别(例如，C统计量)。初级阶段 这项研究的目标是确定慢性肾脏病的个体标志物，并将其合并为预测 算法。慢性肾脏病影响了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CKD在90%的人中直到晚期都是无症状的，早期风险分层可能对 预防ESRD等临床后遗症。中心假设是多基因和甲基化分数 可能能够预测生物学上的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可遗传性 影响健康差距的因素，并开发指导治疗策略的临床工具。 建议的PI培训计划是由她的项目导师Marguerite(Ryan)Irvin博士赞助的。 培训计划中包括帮助PI在以下主要方面发展的经验：1)严谨 慢性病领域的研究，包括熟悉现有的慢性病流行病学文献和 差异、科学诚信原则和负责任的研究行为，以及基因的应用 CKD结果的风险预测；2)遗传流行病学，包括方法学、结果解释和 对已公布的多基因和甲基化风险得分进行批判性评估；以及3)职业和专业 发展，包括学习手稿和赠款撰写、期刊审查、数据介绍和 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 拥有作为一名独立内科科学家的职业生涯的坚实基础，最终目标是领导一个 合作研究团队，弥合健康差距决定因素研究与 实施卫生政策，以改善心血管健康状况。

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.