Pharmacogenomic Evaluation of Antihypertensive Responses

描述（由申请人提供）：这是一项针对RFA-GM-04-002的新申请，这项工作将有助于实现基于患者基因组成选择抗高血压药物治疗的长期目标。高血压（HTN）是最常见的慢性病，也是心脏病发作、中风、肾衰竭和心力衰竭最普遍的危险因素。对降压药物治疗的反应表现出相当大的患者间差异，导致HTN控制率低（目前在美国为34%），以及频繁的不依从和退出治疗。我们提出确定抗高血压和不良代谢反应的遗传预测因子，两种首选和药效学对比的药物，一种受体阻滞剂（阿替洛尔）和一种噻嗪类利尿剂（HCTZ），最初作为单一治疗，随后联合给药，800例无并发症高血压患者。高质量的表型数据，包括血压（BP）反应的家庭和门诊测量，以及不良代谢反应的脂质和胰岛素敏感性测量，将通过两种方法与遗传变异相关。首先，在70个候选基因中分别检测7个snp，我们将检验这些基因变异对p受体阻滞剂和利尿剂反应的影响（Specific Aim 1）。这将包括评估遗传相关性：单药降压反应（Aim 1a），单药治疗中添加第二种药物（Aim 1b）和联合治疗（Aim 1c）；单药和联合治疗的不良代谢反应（Aim Id）。通过对跨越人类基因组的20,000个假定的功能性snp的测试，将发现与可变血压和对p受体阻滞剂和利尿剂的代谢反应有关的新基因，从而补充这种候选基因方法（Specific Aim 2）。与第1阶段一样，第2阶段将包括检测单药和联合治疗与抗高血压和不良代谢反应的相关性。提出的研究将大大增加我们对单一和联合抗高血压药物治疗的药理学遗传学的理解。通过将数据存入PharmGKB，以及创建来自所有研究参与者的永生化细胞系，与其他研究人员共享数据和生物样本，该项目还将创建可供该领域其他人使用的数据集和样本。这项提议的研究意义重大，因为基因靶向降压治疗可能比通常的试错方法产生更高的反应率和更少的副作用。这可能会提高HTN控制率，减少对多种药物的需求，降低卫生保健成本，并改善结果。拟议的努力将通过药物遗传学研究网络的开展得到加强，数据和生物样本的可用性将有利于该领域的其他研究人员。

DESCRIPTION (provided by applicant): This is a new application in response to RFA-GM-04-002, for which the proposed work should help move toward the long-term goal of selection of antihypertensive drug therapy based on a patient's genetic make-up. Hypertension (HTN) is the most common chronic disease for which drugs are prescribed, and the most prevalent risk factor for heart attack, stroke, renal failure and heart failure. Responses to antihypertensive drug therapy exhibit considerable interpatient variability, contributing to poor rates of HTN control (currently 34% in the US), and frequent nonadherence and dropout from therapy. We propose to identify genetic predictors of the antihypertensive and adverse metabolic responses to two preferred and pharmacodynamically contrasting drugs, a ¿-blocker (atenolol) and a thiazide diuretic (HCTZ) given initially as monotherapy, and subsequently in combination, to 800 individuals with uncomplicated hypertension. High quality phenotype data, including both home and ambulatory measures of blood pressure (BP) response, and lipid and insulin sensitivity measures of adverse metabolic responses will be related to genetic variation through two approaches. First, testing 7 SNPs in each of 70 candidate genes, we will examine the influence of these genes' variation on responses to p-blockers and diuretics (Specific Aim 1). This will include assessment of genetic associations with: antihypertensive responses to monotherapy (Aim 1a), addition of a second drug to monotherapy (Aim 1b), and combination therapy (Aim 1c); and adverse metabolic responses to mono and combination therapy (Aim Id). This candidate gene approach will be supplemented by discovery of novel genes involved in variable BP and metabolic responses to p-blockers and diuretics through testing of 20,000 pututative functional SNPs that span the human genome (Specific Aim 2). As in Aim 1, Aim 2 will include testing for associations with antihypertensive and adverse metabolic responses to monotherapy and combination therapy. The proposed research will substantially increase our understanding of the pharmacogenetics of mono- and combination antihypertensive drug therapy. It will also lead to creation of data sets and samples that can be used by others in the field, through deposit of data to PharmGKB, and creation of immortalized cell lines from all study participants to share data and biological samples with other researchers. The proposed research is significant because genetically-targeted antihypertensive therapy could lead to dramatically higher response rates and fewer adverse effects than the usual trial-and-error approach. This would likely lead to higher rates of HTN control, less need for polypharmacy, reduced health care costs, and improved outcomes. The proposed efforts will be enhanced through conduct within the Pharmacogenetics Research Network, and availability of data and biological samples will be beneficial to other investigators in the field.