CLINICAL TRIAL: PHARMACOGENOMIC EVALUATION OF ANTIHYPERTENSIVE RESPONSES PEAR

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 高血压HTN是最常见的药物治疗慢性疾病，也是心脏病发作、中风、肾功能衰竭和心力衰竭的最常见风险因素。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。我们建议确定两种首选的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β-受体阻滞剂阿替洛尔和噻嗪类利尿剂HCTZ，随后联合给予800名无并发症的高血压患者。高质量的表型数据反应、血脂和胰岛素敏感性指标的不良代谢反应将通过两种途径与遗传变异相关。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变异对β-受体阻滞剂和利尿剂反应的影响。这将包括对遗传相关性的评估：单一疗法的抗高血压反应，在单一疗法的基础上添加第二种药物，以及单一疗法和联合疗法的联合疗法和不良代谢反应。对这一候选基因方法的补充是，通过测试跨越人类基因组的20,000个假定的功能性SNP，发现与可变BP以及对β-受体阻滞剂和利尿剂的代谢反应有关的新基因。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。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。

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. We propose to identify genetic predictors of the antihypertensive and adverse metabolic responses to two preferred and pharmacodynamically contrasting drugs, a beta-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 response, 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 beta-blockers and diuretics. This will include assessment of genetic associations with: antihypertensive responses to monotherapy, addition of a second drug to monotherapy, and combination therapy and adverse metabolic responses to mono and combination therapy. This candidate gene approach will be supplemented by discovery of novel genes involved in variable BP and metabolic responses to beta-blockers and diuretics through testing of 20,000 putative functional SNPs that span the human genome. The proposed research will substantially increase our understanding of the pharmacogenetics of mono- and combination antihypertensive drug therapy. This would likely lead to higher rates of HTN control, less need for polypharmacy, reduced health care costs, and improved outcomes.