CLINICAL TRIAL: PHARMACOGENOMIC EVALUATION OF ANTIHYPERTENSIVE RESPONSES PEAR

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目和 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 高血压 HTN 是最常见的需要药物治疗的慢性疾病，也是心脏病、中风、肾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表现出相当大的患者间差异，导致高血压控制率较低。 我们建议确定两种首选且药效学对比药物（β-受体阻滞剂阿替洛尔和噻嗪类利尿剂 HCTZ）的抗高血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疗法，随后联合用药，对 800 名无并发症高血压患者进行治疗。 高质量表型数据反应、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，测试 70 个候选基因中每个基因的 7 个 SNP，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。这将包括评估与以下因素的遗传关联：对单一疗法的抗高血压反应、在单一疗法中添加第二种药物、联合疗法以及对单一和联合疗法的不良代谢反应。 通过测试跨越人类基因组的 20,000 个假定的功能性 SNP，发现涉及可变血压以及对 β 受体阻滞剂和利尿剂的代谢反应的新基因，将补充这种候选基因方法。 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高血压控制率、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. 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.