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

摘要 与美国其他种族相比，非洲裔美国人（AA）的高血压负担过重。 States.这种疾病通常表现为更严重的形式，包括早期发作，对治疗的抵抗， 早期终末器官损伤表明需要个性化的预防医学策略， 在这一组的治疗。观察性研究和临床试验表明， 抗高血压药物在不同种族人群中发挥不同的降压作用。比如说， 与高加索人相比，AAs对β受体阻滞剂、血管紧张素 转换酶抑制剂（ACEI）或血管紧张素受体阻滞剂（ARB），以及对 钙通道阻滞剂（CCB）和利尿剂作为单药治疗。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作为AA的一线降压治疗。然而，数据显示， 种族组内抗高血压治疗类别的反应比种族组间的差异更大， 他们尽管临床上依赖噻嗪类利尿剂治疗AA，但没有大规模的药物遗传学发现 已经作出了努力。此外，人们担心这种药物的代谢副作用 包括糖耐量异常和低钾血症。这对以下患者尤其重要： 非洲血统，谁有患糖尿病的风险较高，往往需要开始治疗，在年轻的 年龄超过一半的已发表的药物遗传学研究不包括AA，并且，在这些研究中， 平均样本量较小（<200）。为了克服以往研究的局限性， 预测血压反应以及代谢反应的基因和变体的遗传发现 我们将利用随机分配至氯噻酮组的4830例AA的数据和标本， 高血压相关治疗遗传学（GenHAT）研究，一项抗高血压药物的辅助研究 降脂治疗预防心脏病发作试验（ALLHAT）。基因组发现将丰富 非洲药典遗传变异、功能变异以及已知的药效学和 药代动力学变量。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）验证我们的研究结果。相关基因 将评估噻嗪类利尿剂反应与AA中心血管疾病结局的相关性， GENHAT和中风研究中地理和种族差异的原因（REGARDS）。总之， 该项目将阐明噻嗪类利尿剂反应的机制;可能确定新的治疗方法 目标;并确定遗传标记，可以优化治疗这一高风险人群。

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.