Genomic Background of Blood Pressure Response to Thiazide Diuretic in African Americans

非裔美国人对噻嗪类利尿剂血压反应的基因组背景

• 批准号: 9351564
• 负责人: Marguerite R Irvin
• 金额: $ 73.36万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 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 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9351564
• 关键词: Adherence; Adrenergic beta-Antagonists; Adverse drug effect; Adverse effects; African; African American; Age; Agreement; Ancillary Study; Angiotensin Receptor; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Bioinformatics; Blood Pressure; Calcium Channel Blockers; Cardiovascular Diseases; Cardiovascular system; Caring; Caucasians; Cessation of life; Chlorthalidone; Clinical; Clinical Trials; Data; Detection; Diabetes Mellitus; Disease; Disease Outcome; Diuretics; Drug Kinetics; Evaluation; Event; Exhibits; Future; Genes; Genetic; Genetic Markers; Genetic Variation; Genetic screening method; Genome; Genomics; Genotype; Goals; High Prevalence; Hypertension; Hypokalemia; Impaired fasting glycaemia; International; Joints; Knowledge; Light; Lipids; Literature; Meta-Analysis; Metabolic; Methods; Myocardial Infarction; Observational Study; Organ; Outcome; Patients; Pharmaceutical Preparations; Pharmacodynamics; Pharmacogenetics; Pharmacogenomics; Phenotype; Population; Population Genetics; Potassium; Prevention; Prevention strategy; Primary Prevention; Publishing; Race; Randomized; Reasons for Geographic And Racial Differences in Stroke; Research; Resistance; Resources; Sample Size; Serum; Specimen; Stroke; Sum; Testing; Thiazide Diuretics; Time; United States; Variant; Weight; base; bead chip; biomarker discovery; blood pressure regulation; cardiovascular disorder prevention; cohort; early onset; familial hypertension; fasting glucose; follow-up; gene discovery; genetic variant; genome sequencing; genome wide association study; genome-wide; glucose tolerance; high risk; high risk population; human disease; improved; inter-individual variation; novel; personalized medicine; premature; prevent; rare variant; response; thiazide; treatment group; validation studies; whole genome

Abstract African Americans (AA) are overburdened with hypertension compared to other racial groups in the United States. The disorder often takes on a more severe form including earlier onset, resistance to treatment, and earlier end organ damage suggesting the need for personalized medicine strategies for prevention and treatment in this group. Observational studies and clinical trials have shown that commonly used antihypertensive agents exert variable blood pressure (BP) lowering effects in ethnic populations. For example, compared to Caucasians, AAs exhibit significantly poorer BP lowering response to beta-blocker, angiotensin converting enzyme inhibitors (ACEIs) or angiotensin receptor blocker (ARB's), and a much better response to calcium channel blockers (CCBs) and diuretics when used as monotherapy. The eighth Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure suggests calcium channel blockers and diuretics should be the first-line antihypertensive therapy for AAs. However, data show there is more variation in response to antihypertensive treatment classes within race groups than between them. Despite the clinical reliance on thiazide diuretics for AAs, no large scale pharmacogenetic discovery effort has been undertaken. Furthermore, there are concerns regarding metabolic side effects for this drug class, including abnormal glucose tolerance and hypokalemia. This is of particular importance to patients of African ancestry, who have a higher risk of developing diabetes, and often need to start treatment at a younger age. More than half of published pharmacogenetic studies do not include AAs, and, among those that do, the average sample size is small (<200). In order to overcome the limitations of previous research and enable genetic discovery of genes and variants which predict blood pressure response as well as metabolic response to thiazide diuretic, we will leverage data and specimens from 4830 AAs randomized to chlorthalidone from the Genetics of Hypertension Associated Treatment (GenHAT) study, an ancillary study of the Antihypertensive and Lipid lowering Treatment to Prevent Heart Attack Trial (ALLHAT). Genomic discovery will be enriched for African Ancestry genetic variations, functional variation, as well as known pharmacodynamic and pharmacokinetic variants. We have established an agreement with the International Consortium for Antihypertensives Pharmacogenomics Studies (ICAPS) for validation of our findings. Genes associated with thiazide diuretic response will be evaluated for association with cardiovascular disease outcomes in AAs from GENHAT and the Reasons for Geographic and Racial Differences in Stroke Study (REGARDS). In sum, the project will shed light on the mechanisms of thiazide diuretic response; potentially identify new treatment targets; and identify genetic markers which can optimize treatment in this high risk population.

抽象的 与联合的其他种族群体相比 国家。该疾病通常采取更严重的形式，包括早期发作，对治疗的抵抗力以及 较早的器官损伤表明需要进行个性化医学策略以进行预防和 该组的治疗。观察性研究和临床试验表明，通常使用 降压药在民族种群中发挥可变的血压（BP）降低作用。例如， 与高加索人相比，AAS表现出明显较差的BP降低对β受体阻滞剂，血管紧张素的反应 转换酶抑制剂（ACEI）或血管紧张素受体阻滞剂（ARB），对 用作单一疗法时，钙通道阻滞剂（CCB）和利尿剂。第八联合国民 高血压预防，检测，评估和治疗委员会表明钙 通道阻滞剂和利尿剂应成为AAS的一线降压治疗。但是，数据显示 响应种族组内的降压治疗类别的差异要大于 他们。尽管临床依赖于AAS的噻嗪类利尿剂，但没有大规模的药物遗传学发现 已经努力了。此外，人们对这种药物的代谢副作用有担忧 类别，包括异常的葡萄糖耐受性和低钾血症。这对于患者 非洲血统，患糖尿病的风险较高，通常需要在年轻人中开始治疗 年龄。超过一半的已发表的药物遗传学研究不包括AA，在那些中， 平均样本量很小（<200）。为了克服先前研究的局限性并启用 基因和变体的遗传发现，这些基因和变体预测血压反应以及代谢反应 对于噻嗪类利尿剂，我们将利用从4830 AA的数据和标本从随机分配到氯噻酮的4830个标本 高血压相关治疗的遗传学（Genhat）研究，抗高血压的辅助研究 和脂质降低治疗以防止心脏病发作试验（Allhat）。基因组发现将被丰富 非洲血统遗传变异，功能变异以及已知的药效学和 药代动力学变体。我们已经与国际财团建立了协议 抗高素质药物基因组学研究（ICAP）用于验证我们的发现。与之相关的基因 将评估噻嗪类利尿反应与AAS中心血管疾病结果相关的AA Genhat和中风研究中地理和种族差异的原因（有关）。总而言之 项目将阐明噻嗪类利尿反应的机制；潜在地识别新疗法 目标；并确定可以在此高风险人群中优化治疗的遗传标记。