Anthipertensive PharmacoGenomics

描述(由申请人提供)： 高血压是一种常见的疾病，会导致发病率、死亡率和医疗费用，特别是在非裔美国人中。尽管有多种抗高血压药物，作用于各种血压调节系统，但只有不到40%的接受治疗的患者实现了血压控制。这项应用的总体目标是超越选定的候选基因研究，对影响降压药物反应的未知基因进行全基因组评估。通过确定新的药物反应基因，拟议的药物基因组学研究有可能使个体患者的降压治疗更加有效。抗高血压药物反应的遗传流行病学(GERA)研究(R01 HL 53330)正在确定肾素-血管紧张素-醛固酮系统和肾脏钠转运系统的候选基因多态性，这些基因多态可以预测社区高血压非裔美国人和非西班牙裔白人对噻嗪利尿剂(方案1)和血管紧张素II受体阻滞剂(方案2)的BP反应。然而，要解释BP反应的充分变异在临床上是有用的，需要一种全球性的药物基因组学方法。因此，降压药物反应的测量和GERA储存的DNA将用于实现以下具体目标： 目的：利用单核苷酸多态的全基因组关联分析，在先前登记在GERA方案1中的非裔美国人(n=200)和非西班牙裔白人(n=200)中，确定影响血压对噻嗪类利尿剂反应的新基因。 目的：在GERA方案2中登记的非裔美国人(n=200)和非西班牙裔白人(n=200)中，使用单核苷酸多态的全基因组关联分析来确定影响血压对血管紧张素II受体阻滞剂反应的新基因。 目的3：在来自AIMS 1和AIMS 2的400名高血压非裔美国人和400名非西班牙裔白人的组合样本中，确定与噻嗪利尿剂的BP反应相关的基因组变异与血管紧张素II受体阻滞剂的BP反应相关的基因组变异是否不同。

DESCRIPTION (provided by applicant): Essential hypertension (hypertension) is a common disorder that contributes to morbidity, mortality, and cost of health care, especially among African-Americans. Despite availability of multiple antihypertensive drugs, acting on a variety of blood pressure (BP)-regulating systems, less than 40% of treated patients achieve BP control. The overall objective of this application is to advance beyond selected candidate gene studies to entire genome assessment for as yet unknown genes influencing antihypertensive drug responses. By identifying novel drug-response genes, the proposed pharmacogenomic study has the potential to enable more effective tailoring of antihypertensive therapy in individual patients. The Genetic Epidemiology of Responses to Antihypertensives (GERA) study (R01 HL 53330) is identifying candidate gene polymorphisms of the renin-angiotensin-aldosterone system and renal sodium transport systems that predict BP responses to a thiazide diuretic (protocol 1) and to an angiotensin II receptor blocker (protocol 2) in community-based hypertensive African-Americans and non-Hispanic whites. However, explaining sufficient variation in BP responses to be clinically useful requires a global, pharmacogenomic approach. Accordingly, measurements of antihypertensive drug responses and stored DNA from GERA will be used to accomplish the following specific aims: Aim 1: Use genome-wide association analyses of single nucleotide polymorphisms to identify novel genes influencing BP response to a thiazide diuretic in hypertensive African-Americans (n = 200) and non-Hispanic whites (n = 200) previously enrolled in GERA protocol 1. Aim 2: Use genome-wide association analyses of single nucleotide polymorphisms to identify novel genes influencing BP response to an angiotensin II receptor blocker in hypertensive African-Americans (n = 200) and non-Hispanic whites (n = 200) enrolled in GERA protocol 2. Aim 3: Determine whether genomic variations associated with BP response to a thiazide diuretic differ from those associated with BP response to an angiotensin II receptor blocker in the combined samples of 400 hypertensive African-Americans and 400 non-Hispanic whites from aims 1 and 2.