Genetic ancestry and antihypertensive medication responses in African Americans

项目摘要/摘要 高血压(HTN)是美国心血管疾病(CVD)的主要可改变原因，影响了80%的人 100万美国人，每年花费超过450亿美元。HTN对非洲有深远的、不成比例的影响 美国人(AA)。我寻求导师研究职业发展奖的目标是获得 必要的培训、实践经验和知识，以发展校长的研究生涯 研究人员专注于通过使用这种组合的科学发现来减少健康差距 药物流行病学(人群中的药物效应)和药物基因组学(遗传原因 不同的药物效果)。 为了继续朝着这个目标前进，这个项目的目标是确定两者之间的联系 遗传祖先，包括个体基因变异，有血压控制，降压药物 腹主动脉系统的反应和心血管疾病结局。鉴于观察到的抗高血压药物的种族差异 作为回应，中心假设是HTN控制方面的种族差异与长期后遗症有关 对降压药物反应的遗传差异，特别是血管紧张素转换 酶抑制剂。这个项目的基本原理是，遗传祖先将识别遗传因素 为抗高血压药物反应的种族差异提供了一个框架 抗高血压治疗的个性化方法。同时，它将提供手段来放置 我走上了研究生涯的轨道，成为一名专注于减少健康差距的首席研究员 采用药物流行病学和药物基因组学相结合的方法。 为了测试中心假设并实现此应用程序的目标，我将追求以下内容 三个具体目标：1)通过以下方式建立AAS的遗传祖先和血压控制之间的联系 用药类别；2)确定基因祖先是否改变了降压药对心血管疾病的影响 AAS中的事件；以及3)确定改善非裔美国人血压控制的机会 退伍军人。我将利用美国心脏协会的三个队列：(1)杰克逊心脏研究(JHS)：一项专门针对非洲人的大型研究 美国队列研究(n=5,301)，包含详细的遗传、临床和社会经济地位(SES)变量，(2) 抗高血压和降脂治疗预防心脏病发作试验(ALLHAT)：一项大型试验(n=42,419) 比较四种降压药对心血管事件的疗效的随机试验(RCT)，以及(3) 退伍军人管理信息学和计算基础设施(Vinci)：一个包含患者数据的数据库 包括所有退伍军人的药物索赔、电子健康记录和行政索赔(n=~900万)。 这一贡献是表征基因作用的一系列研究的重要的第一步 血统，包括个体基因变异，在HTN治疗中。这一点意义重大，因为它可能会改变 最初如何治疗腹主动脉硬化(例如，指导选择最初的降压药[S])，导致 减少HTN结果中的种族差异，并与联邦政府在以人口为基础的投资方面保持一致， 精准医疗促进健康公平。 这项拟议的研究具有创新性，其重点是利用遗传祖先来表征 腹主动脉粥样硬化症患者的降压药物反应和结局。到目前为止，绝大多数的研究 确定了自我报告的AAS和高加索人之间的反应差异。检查药物之间的差异 在遗传祖先范围内AAs的反应受到的关注要少得多，HTN方面还没有研究 到目前为止。这项工作代表了研究方法的转变，即理解 抗高血压药物治疗的反应和结果。 为了实现我的长期目标和这项建议的目标，我将需要以下方面的培训和指导： (1)遗传血统分析，(2)RCT遗传子研究分析，(3)心血管 药物流行病学，(4)健康差距，和(5)主要研究人员的领导技能。这样的训练， 作为对心血管药物遗传学和临床药学现有专业知识的补充，将 通过高度专注的课程学习、丰富的研究经验和积极的学习 辅导。应聘者的指导团队均为国际公认的专家，长期成功 拥有所有必要知识和技能的资助和见习导师的跟踪记录， 成功。我的导师团队包括遗传学和混合体专家(林恩·乔德博士、里克·基特尔斯博士)， 药物流行病学和HTN(Paul Muntner和Rachel Hess博士)，药物遗传学(Donna Arnett博士) 和生物统计学(汤姆·格林博士)。我的团队拥有广泛的专业知识，可以帮助我获得关键的 多学科技能，并成功地实现了我的研究目标。密歇根大学的环境 犹他州是我过渡到独立的理想环境。总而言之，我以前的训练和经验， 创新的研究计划、高质量的培训计划、一流的导师团队和支持性研究 环境给了我最高的成功可能性，研究独立与建议的K01 获奖。

PROJECT SUMMARY/ABSTRACT Hypertension (HTN) is the leading modifiable cause of cardiovascular disease (CVD) in the US, affecting 80 million Americans and costing over $45 billion annually. HTN has profound, disproportionate effects on African Americans (AAs). My goal in seeking a Mentored Research Career Development Award is to acquire the necessary training, practical experience, and knowledge to develop a research career as a principal investigator focused on reducing health disparities through scientific discoveries made using the combination of pharmacoepidemiology (medication effects in populations) and pharmacogenomics (genetic causes of variable medication effects). To continue my progress towards this goal, the objective of this project is to determine the association between genetic ancestry, including individual genetic variants, with blood pressure control, antihypertensive medication responses, and CVD outcomes in AAs. Given the observed racial differences in antihypertensive medication response, the central hypothesis is that the racial disparities in HTN control and long-term sequelae are related to genetic differences in the response to antihypertensive medications, particularly angiotensin converting enzyme inhibitors. The rationale for this project is that genetic ancestry will identify genetic factors accounting for racial differences in antihypertensive medication responses and provide a framework for the development of personalized approaches to antihypertensive treatment. At the same time, it will provide the means to place me on a trajectory towards a research career as a principal investigator focused on reducing health disparities using the combination of pharmacoepidemiology and pharmacogenomics. To test the central hypothesis and accomplish the objectives for this application, I will pursue the following three specific aims: 1) Establish the association of genetic ancestry and blood pressure control in AAs by medication class; 2) Determine if genetic ancestry modifies the effect of antihypertensive medications on CVD events in AAs; and 3) Identify opportunities to improve blood pressure control among African American Veterans. I will utilize three cohorts of AAs: (1) Jackson Heart Study (JHS): a large exclusively African American cohort study (n=5,301) with detailed genetic, clinical, and socioeconomic status (SES) variables, (2) Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT): a large (n=42,419) randomized trial (RCT) comparing the efficacy of four antihypertensive medications on CVD events, and (3) Veterns Administration Informatics and Computing Infrastructure (VINCI): a database with patient data including medication claims, electronic health records, and administrative claims for all Veterans (n=~9 million). This contribution is a significant first step in a continuum of research that characterizes the role of genetic ancestry, including individual genetic variants, in HTN treatment. This is significant because it may transform how AAs are initially treated, (e.g., guiding the choice of initial antihypertensive medication[s]), resulting in reduced racial disparities in HTN outcomes and aligning with federal investments in population-based, precision medicine approaches to improve health equity. The proposed research is innovative in its focuses on the use of genetic ancestry to characterize differences in antihypertensive medication responses and outcomes among AAs. The vast majority of research to date identified differences in response between self-reported AAs and Caucasians. Examining differences in drug response within AAs across ranges of genetic ancestry has received far less attention, with no studies in HTN to date. This work represents a shift in the research approach to understanding racial differences in antihypertensive medication treatment responses and outcomes. In order to obtain my long-term goal and the objective of this proposal, I will require training and mentorship in: (1) genetic ancestry analyses, (2) analysis of genetic sub-studies of RCTs, (3) cardiovascular pharmacoepidemiology, (4) health disparities, and (5) leadership skills for principal investigators. Such training, which complements existing expertise in cardiovascular pharmacogenetics and clinical pharmacy, will be achieved through a combination of highly focused coursework, significant research experience, and active mentoring. The Candidate's mentoring team is all internationally recognized experts with long and successful track records of funding and trainee mentorship who possess all the necessary knowledge and skills, for success. My mentorship team includes experts in genetics and admixture (Drs. Lynn Jorde, Rick Kittles), pharmacoepidemiology and HTN (Drs. Paul Muntner and Rachel Hess), pharmacogenetics (Dr. Donna Arnett) and biostatistics (Dr. Tom Greene). My team has the breadth of expertise to help me obtain critical multidisciplinary skills and successfully implement my research aims. The environment at the University of Utah is an ideal setting for me to transition to independence. In summary, my previous training and experience, innovative research plan, high-quality training plan, first-rate mentorship team, and supportive research environment give me the highest likelihood of success to research independence with the proposed K01 award.