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: 10165079
• 负责人: Marguerite R Irvin
• 金额: $ 4.68万
• 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 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10165079
• 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; 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; Evaluation; Event; Exhibits; Future; Genes; Genetic; Genetic Markers; Genetic Variation; 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; 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; Sample Size; Serum; Specimen; Stroke; Sum; Testing; Thiazide Diuretics; Time; United States; Variant; Weight; base; bead chip; bioinformatics resource; biomarker discovery; blood pressure regulation; cardiovascular disorder prevention; cohort; early onset; familial hypertension; fasting glucose; follow-up; gene discovery; genetic testing; 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; pharmacokinetics and pharmacodynamics; premature; prevent; rare variant; response; side effect; thiazide; treatment group; treatment optimization; 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 与美国其他种族群体相比，非洲裔美国人 (AA) 的高血压负担过重 国家。这种疾病通常表现为更严重的形式，包括发病较早、对治疗有抵抗力和 较早的终末器官损伤表明需要个性化的医学策略来预防和治疗 本组治疗。观察研究和临床试验表明，常用的 抗高血压药物对不同种族人群具有不同程度的降低血压（BP）的作用。例如， 与白种人相比，AA 对 β 受体阻滞剂、血管紧张素的降压反应明显较差 转换酶抑制剂（ACEIs）或血管紧张素受体阻滞剂（ARB），以及更好的反应 钙通道阻滞剂（CCB）和利尿剂作为单一疗法使用时。第八届全国联合 高血压预防、检测、评估和治疗委员会建议钙 通道阻滞剂和利尿剂应该是 AA 的一线降压治疗。然而，数据显示 不同种族之间对抗高血压治疗类别的反应差异更大 他们。尽管临床上依赖噻嗪类利尿剂来治疗 AA，但尚未发现大规模的药物遗传学发现 已经做出了努力。此外，人们还担心这种药物的代谢副作用 类，包括糖耐量异常和低钾血症。这对于以下患者尤为重要 非洲血统，患糖尿病的风险较高，通常需要在更年轻的时候开始治疗 年龄。超过一半已发表的药物遗传学研究不包括 AA，并且在那些包括 AA 的研究中， 平均样本量较小（<200）。为了克服以往研究的局限性并实现 预测血压反应和代谢反应的基因和变异的遗传发现 对于噻嗪类利尿剂，我们将利用来自 4830 个 AA 的数据和样本，这些 AA 随机分配到氯噻酮 高血压相关治疗遗传学（GenHAT）研究，抗高血压药物的辅助研究 和降脂治疗预防心脏病试验（ALLHAT）。基因组发现将更加丰富 非洲血统的遗传变异、功能变异以及已知的药效学和 药代动力学变异。我们已与国际财团达成协议 抗高血压药物基因组学研究 (ICAPS) 用于验证我们的研究结果。相关基因 将评估噻嗪类利尿反应与 AA 中心血管疾病结局的关系 GENHAT 和中风研究中地理和种族差异的原因（REGARDS）。总而言之， 该项目将阐明噻嗪类利尿反应的机制；可能确定新的治疗方法 目标；并确定可以优化这一高危人群治疗的遗传标记。