Anthipertensive PharmacoGenomics

描述（由申请人提供）： 原发性高血压（高血压）是一种常见的疾病，导致发病率，死亡率和医疗费用，特别是在非洲裔美国人中。尽管有多种抗高血压药物，作用于各种血压（BP）调节系统，但只有不到40%的治疗患者实现了BP控制。本申请的总体目标是超越选定的候选基因研究，对影响抗高血压药物反应的未知基因进行全基因组评估。通过识别新的药物反应基因，拟议的药物基因组学研究有可能使个体患者更有效的抗高血压治疗。抗高血压药物反应的遗传流行病学（GERA）研究（R 01 HL 53330）正在确定肾素-血管紧张素-醛固酮系统和肾钠转运系统的候选基因多态性，这些基因多态性可预测社区高血压非裔美国人和非西班牙裔白人对噻嗪类利尿剂（方案1）和血管紧张素II受体阻滞剂（方案2）的血压反应。然而，解释足够的变化，BP反应是临床上有用的，需要一个全球性的，药物基因组学的方法。因此，抗高血压药物反应的测量和来自GERA的储存DNA将用于实现以下特定目标： 目标1：使用单核苷酸多态性的全基因组关联分析，以确定影响高血压非洲裔美国人（n = 200）和非西班牙裔白人（n = 200）中的血压反应噻嗪类利尿剂的新基因先前在GERA协议1。 目标二：使用单核苷酸多态性的全基因组关联分析，以确定影响高血压非洲裔美国人（n = 200）和非西班牙裔白人（n = 200）中的血压反应血管紧张素II受体阻滞剂的新基因入组GERA方案2。 目标3：在目标1和目标2的400例高血压非裔美国人和400例非西班牙裔白人的合并样本中，确定与噻嗪类利尿剂的BP反应相关的基因组变异是否与血管紧张素II受体阻滞剂的BP反应相关的基因组变异不同。

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.