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.

项目摘要/摘要 高血压（HTN）是美国心血管疾病（CVD）的主要修改原因，影响80 百万美国人，每年耗资超过450亿美元。 HTN对非洲人有深远的，不成比例的影响 美国人（AAS）。我寻求指导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，以发展研究职业 研究人员致力于通过使用该组合做出的科学发现来降低健康差异 药物epidemiology（种群中的药物作用）和药物基因组学（遗传原因 可变药物效果）。 为了继续我朝着这个目标的进步，该项目的目的是确定 遗传血统，包括各个遗传变异，具有血压控制，降压药 AAS中的响应和CVD结果。鉴于观察到的降压药的种族差异 反应，中心假设是HTN控制和长期后遗症的种族差异是相关的 在对降压药的反应中的遗传差异，尤其是血管紧张素转化 酶抑制剂。该项目的理由是遗传血统将确定遗传因素会计 对于降压药物反应的种族差异，并为开发提供了框架 个性化方法的降压治疗方法。同时，它将提供放置的手段 我是一名主要研究人员，致力于减少健康差异的轨迹 结合了药物epidemiology和药物基因组学。 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 三个具体目的：1）通过 药物类； 2）确定遗传血统是否改变了降压药对CVD的影响 AAS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。我将利用三个AAS组：（1）杰克逊心脏研究（JHS）：一个大型非洲人 美国队列研究（N = 5,301）具有详细的遗传，临床和社会经济状况（SES）变量，（2） 降压和脂质降低治疗以防止心脏病发作试验（allhat）：大（n = 42,419） 比较四种降压药对CVD事件的疗效的随机试验（RCT），以及（3） Veterns管理信息学和计算基础设施（VINCI）：带有患者数据的数据库 包括药物索赔，电子健康记录和所有退伍军人的行政索赔（n = 〜900万）。 这种贡献是连续研究的重要第一步，该研究表征了遗传的作用 HTN治疗中的祖先，包括各个遗传变异。这很重要，因为它可能会改变 最初如何处理AAS（例如，指导最初的降压药[S]），导致 HTN成果的种族差异降低，并与联邦对基于人群的， 精确医学方法以改善健康公平。 拟议的研究的重点是使用遗传血统来表征差异 AAS中的降压药反应和结果。迄今为止的绝大多数研究 确定自我报告的AAS和高加索人之间的反应差异。检查药物的差异 跨遗传血统范围内AAS内的反应已受到较少的关注，没有HTN的研究 迄今为止。这项工作代表了研究方法的转变，以理解种族差异 降压药物治疗反应和结果。 为了获得我的长期目标和该提案的目标，我将需要培训和指导： （1）遗传血统分析，（2）RCT的遗传亚研究分析，（3）心血管 药ePidemiology，（4）健康差异和（5）首席研究人员的领导能力。这样的培训， 这补充了心血管药物遗传学和临床药房的现有专业知识，将是 通过高度集中的课程，丰富的研究经验和积极的结合来实现 指导。候选人的指导团队都是国际认可的专家 具有资金和学员指导的记录，他们拥有所有必要的知识和技能 成功。我的指导团队包括遗传学和混合物的专家（Lynn Jorde博士，Rick Kittles）， 药ePidemiology and 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）。我的团队具有广度的专业知识，可以帮助我获得关键 多学科技能并成功地实施了我的研究目标。大学的环境 犹他州是我过渡到独立性的理想环境。总而言之，我以前的培训和经验， 创新研究计划，高质量培训计划，一流的指导团队和支持性研究 环境给我带来最大的成功研究独立的可能性 奖。