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

摘要 与美国其他种族群体相比，非裔美国人(AA)的高血压负担过重 各州。这种疾病通常表现出更严重的形式，包括发病较早，对治疗产生抵抗，以及 更早结束器官损伤表明需要个性化的药物策略来预防和 在这个组中进行治疗。观察研究和临床试验表明，常用的 抗高血压药物在少数民族人群中具有不同的降压作用。例如, 与高加索人相比，AAS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(ACEI)或血管紧张素受体阻滞剂(ARB)，以及对 钙通道阻滞剂(CCB)和利尿剂作为单一疗法使用。第八次全国联合 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腹主动脉硬化的一线抗高血压药物。然而，数据显示 种族间对抗高血压治疗类别的反应差异较大。 他们。尽管临床上依赖噻嗪类利尿剂治疗腹主动脉硬化，但没有大规模的药物遗传学发现 已经做出了努力。此外，这种药物的代谢副作用也令人担忧。 类，包括糖耐量异常和低钾血症。这一点对患有 非洲血统，他们患糖尿病的风险更高，通常需要从更年轻的人开始治疗 年龄。超过一半的已发表的药物遗传学研究不包括AAs，而在那些包含AAs的研究中， 平均样本量很小(200英镑)。为了克服以往研究的局限性并使 预测血压反应和代谢反应的基因和变异的遗传发现 对于噻嗪利尿剂，我们将利用从4830个AA中随机抽取的数据和样本，从 高血压相关治疗的遗传学研究(GenHAT)，抗高血压的辅助研究 和降脂治疗预防心脏病发作试验(ALLHAT)。基因组发现将丰富 非洲血统的遗传变异，功能变异，以及已知的药效学和 药代动力学变种。我们已经与国际财团达成了一项协议 抗高血压药物药物基因组学研究(ICAPS)以验证我们的发现。与之相关的基因 将评估噻嗪利尿剂的反应与AAS患者心血管疾病结局的相关性 GENHAT与卒中地理和种族差异的原因研究(有关)。总而言之， 该项目将阐明噻嗪类利尿剂反应的机制；可能会发现新的治疗方法 目标；并确定可以在这一高危人群中优化治疗的遗传标记。

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.