PHARMACOGENOMIC EVALUATION OF ANTIHYPERTENSIVE RESPONSES (PEAR)

该子项目是利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得主要资金， 因此可以在其他CRISP条目中表示。列出的机构是 中心，不一定是研究者的机构。 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。我们建议确定遗传预测的抗高血压和不良代谢反应的两个首选和药效学对比的药物，α-受体阻滞剂（阿替洛尔）和噻嗪类利尿剂（HCTZ）最初作为单一疗法，随后在组合，800个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1d）。 这种候选基因的方法将通过发现新的基因参与变量BP和代谢反应的阻断剂和利尿剂，通过测试20,000个假定的功能SNP，跨越人类基因组（具体目标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。 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。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. 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 non-adherence 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 -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 1d). This candidate gene approach will be supplemented by discovery of novel genes involved in variable BP and metabolic responses to -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. 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.