Pharmacogenomic Evaluation of Antihypertensive Responses

描述(由申请人提供)：这是一项响应RFA-GM-04-002的新申请，对于该申请，拟议的工作应有助于朝着基于患者基因构成选择抗高血压药物的长期目标迈进。高血压(HTN)是最常见的慢性疾病，也是心脏病发作、中风、肾功能衰竭和心力衰竭最常见的危险因素。抗高血压药物治疗的反应在患者之间表现出相当大的差异性，导致HTN控制率较低(目前在美国为34%)，以及频繁的不依从性和退出治疗。我们建议确定两种首选和药效学对比药物的降压和不良代谢反应的遗传预测因子，这两种药物最初作为单一治疗给予阿替洛尔和噻嗪类利尿剂(HCTZ)，然后联合给予800名无并发症的高血压患者。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血脂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，检测70个候选基因中每个基因的7个SNPs，我们将检查这些基因的变异对P-受体阻滞剂和利尿剂的反应的影响(特定目标1)。这将包括对以下方面的遗传相关性的评估：单一疗法的降压反应(目标1a)、在单一疗法的基础上添加第二种药物(目标1b)和联合疗法(目标1c)；以及单一疗法和联合疗法的不良代谢反应(目标ID)。对这一候选基因方法的补充将是通过测试跨越人类基因组的20,000个假定的功能性SNP，发现涉及可变BP和对p-受体阻滞剂和利尿剂的代谢反应的新基因(特定目标2)。与目标1一样，目标2将包括测试与抗高血压和单一疗法和联合疗法的不良代谢反应之间的关系。这项拟议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物遗传学的理解。它还将导致创建可供该领域其他人使用的数据集和样本，方法是将数据存放到PharmGKB，并创建来自所有研究参与者的永生化细胞系，以便与其他研究人员共享数据和生物样本。这项拟议的研究意义重大，因为与通常的反复试验方法相比，基因靶向降压治疗可以导致显著更高的应答率和更少的不良反应。这可能会导致更高的HTN控制率，更少的多药需求，更低的医疗成本，以及更好的结果。拟议的努力将通过在药物遗传学研究网络内进行而得到加强，数据和生物样本的提供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.