Genetic ancestry and antihypertensive medication responses in African Americans

非裔美国人的遗传血统和抗高血压药物反应

• 批准号: 9162980
• 负责人: Adam P Bress
• 金额: $ 16.55万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-15 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9162980
• 关键词: Accounting; Adherence; Admixture; Affect; African; African American; Aftercare; American; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Applications Grants; Attention; Award; Biometry; Blood Pressure; Body mass index; Calcium Channel Blockers; Cardiovascular Diseases; Cardiovascular system; Caucasians; Clinical; Cohort Studies; Comorbidity; Complement; Data; Data Set; Databases; Death Rate; Development; Development Plans; Diet; Disease Outcome; Electronic Health Record; Environment; European; Event; Funding; Future; Genetic; Goals; Guidelines; High Prevalence; Hypertension; Individual; Informatics; Investigation; Investments; Jackson Heart Study; Joints; K-Series Research Career Programs; Knowledge; Lead; Leadership; Lipids; Medical Genetics; Mentored Research Scientist Development Award; Mentors; Mentorship; Methods; Myocardial Infarction; Naltrexone; Outcome; Participant; Patient Self-Report; Patients; Pharmaceutical Preparations; Pharmacoepidemiology; Pharmacogenetics; Pharmacogenomics; Pharmacy facility; Physical activity; Population; Positioning Attribute; Prevalence; Principal Investigator; Public Health; Randomized Clinical Trials; Records; Regimen; Renin-Angiotensin-Aldosterone System; Research; Research Infrastructure; Role; Socioeconomic Status; Stress; Testing; Thiazide Diuretics; Time; Training; Treatment outcome; Universities; Utah; Variant; Veterans; Work; admixture mapping; base; blood pressure regulation; career; career development; cohort; comparative efficacy; cost; experience; genetic analysis; genetic association; genetic variant; health disparity; health equity; hypertension control; hypertension treatment; improved; innovation; multidisciplinary; novel strategies; personalized approach; population based; precision medicine; prevent; racial difference; racial disparity; randomized trial; research and development; response; skills; smoking cessation; success; targeted agent; treatment effect; treatment response; trial comparing

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.

项目概要/摘要 高血压 (HTN) 是美国心血管疾病 (CVD) 的首要可改变病因，影响 80 百万美国人，每年花费超过 450 亿美元。 HTN 对非洲产生了深远且不成比例的影响 美国人（AA）。我寻求指导研究职业发展奖的目标是获得 作为校长发展研究生涯所需的培训、实践经验和知识 研究人员致力于通过使用该组合的科学发现来减少健康差异 药物流行病学（药物对人群的影响）和药物基因组学（遗传原因） 不同的药物作用）。 为了继续实现这一目标，该项目的目标是确定之间的关联 遗传血统，包括个体遗传变异，与血压控制、抗高血压药物 AA 中的反应和 CVD 结果。鉴于观察到的抗高血压药物的种族差异 反应，中心假设是 HTN 控制的种族差异与长期后遗症相关 对抗高血压药物反应的遗传差异，特别是血管紧张素转换 酶抑制剂。该项目的基本原理是遗传血统将识别遗传因素核算 抗高血压药物反应中的种族差异，并为开发提供框架 个性化的抗高血压治疗方法。同时，它将提供放置的手段 作为一名主要研究人员，我正走在研究生涯的轨道上，专注于减少健康差距 结合药物流行病学和药物基因组学。 为了检验中心假设并实现此应用程序的目标，我将追求以下目标 三个具体目标： 1) 通过以下方式建立 AA 中遗传血统与血压控制的关联： 药物类； 2) 确定遗传血统是否会改变抗高血压药物对心血管疾病的影响 AA 中的活动； 3) 确定改善非裔美国人血压控制的机会 退伍军人。我将利用三组 AA：(1) 杰克逊心脏研究 (JHS)：一项大型的专属非洲研究 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试验 (ALLHAT)：大型 (n=42,419) 比较四种抗高血压药物对 CVD 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)：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=约 900 万）。 这一贡献是表征遗传作用的连续研究中重要的第一步。 HTN 治疗中的血统，包括个体遗传变异。这很重要，因为它可能会改变 AA 最初如何治疗（例如，指导初始抗高血压药物的选择），导致 减少 HTN 结果的种族差异，并与联邦对基于人口的投资保持一致， 精准医疗方法可改善健康公平。 拟议的研究具有创新性，其重点是利用遗传血统来表征差异 AA 之间的抗高血压药物反应和结果。迄今为止的绝大多数研究 确定了自我报告的 AA 和白人之间的反应差异。检查药物的差异 跨遗传祖先范围的 AA 内的反应受到的关注要少得多，没有针对 HTN 的研究 迄今为止。这项工作代表了理解种族差异的研究方法的转变 抗高血压药物治疗反应和结果。 为了实现我的长期目标和本提案的目标，我将需要以下方面的培训和指导： (1) 遗传谱系分析，(2) 随机对照试验的遗传子研究分析，(3) 心血管 药物流行病学，(4) 健康差异，以及 (5) 主要研究者的领导技能。这样的训练， 它补充了心血管药物遗传学和临床药学的现有专业知识，将 通过高度集中的课程作业、丰富的研究经验和积极的 指导。候选人的指导团队都是具有长期成功经验的国际公认专家 跟踪拥有所有必要知识和技能的资金和实习生指导记录， 成功。我的导师团队包括遗传学和混合专家（Lynn Jorde 博士、Rick Kittles）、 药物流行病学和 HTN（Paul Muntner 博士和 Rachel Hess）、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 多学科技能并成功实现我的研究目标。大学环境 犹他州是我过渡到独立的理想环境。总结一下我之前的训练和经历， 创新的研究计划、高质量的培养计划、一流的导师团队、支持性的研究 环境给了我最大的可能性通过拟议的 K01 进行独立研究 奖。