Pharmacogenomic Evaluation of Antihypertensive Responses

描述（由申请人提供）：这是响应RFA-GM-04-002的新申请，其拟定工作应有助于实现基于患者遗传组成选择抗高血压药物治疗的长期目标。高血压（HTN）是最常见的慢性疾病，药物处方，以及心脏病发作，中风，肾衰竭和心力衰竭的最普遍的危险因素。抗高血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治疗脱落。我们建议确定抗高血压和不良代谢反应的遗传预测两个首选的和药效学上的对比药物，阿替洛尔（阿替洛尔）和噻嗪类利尿剂（HCTZ）最初作为单药治疗，随后在组合中，800人与无并发症的高血压。高质量的表型数据，包括家庭和动态血压（BP）反应的测量，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个候选基因中的每一个中测试7个SNP，我们将检查这些基因的变异对对β-受体阻滞剂和利尿剂的反应的影响（具体目标1）。这将包括评估与以下因素的遗传相关性：单药治疗的降压反应（目标1a）、单药治疗中添加第二种药物（目标1b）和联合治疗（目标1c）;以及单药和联合治疗的不良代谢反应（目标Id）。通过检测20，000个跨越人类基因组的推定功能SNP，发现参与可变BP和对β受体阻滞剂和利尿剂的代谢反应的新基因，补充了这种候选基因方法（特定目标2）。与目标1相同，目标2将包括检测单药治疗和联合治疗与抗高血压和不良代谢反应的相关性。这项研究将大大增加我们对单用和联合降压药物治疗的遗传药理学的理解。它还将通过将数据存款PharmGKB，创建可供该领域其他人使用的数据集和样本，并创建来自所有研究参与者的永生化细胞系，以与其他研究人员共享数据和生物样本。这项研究是重要的，因为基因靶向抗高血压治疗可能会导致显着更高的反应率和更少的不良反应比通常的试错法。这可能会导致更高的HTN控制率，减少对多种药物的需求，降低医疗保健成本，并改善结果。通过在药物遗传学研究网络内开展工作，将加强拟议的努力，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.