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%)，以及频繁的不坚持和退出治疗。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α-受体阻滞剂(阿替洛尔)和一种噻嗪利尿剂(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阻滞剂和利尿剂反应的影响(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1d)。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(特定目标2)，发现涉及可变BP以及对阻滞剂和利尿剂的代谢反应的新基因。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。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。

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.