Pharmacogenomic Evaluation of Antihypertensive Responses

描述（由申请人提供）： 高血压（HTN）使超过7000万美国人（以及全球约10亿人）处于中风、心脏病发作、肾衰竭和心力衰竭的显著增加的风险中，并且是最常见的慢性疾病，为此开了药物。对于HTN有许多可接受的一线治疗选择，然而对于给定患者的特定药物的选择是经验性的，仅约50%的患者使用给定的抗高血压药物具有可接受的血压（BP）降低，一些患者经历不良代谢作用并由于其治疗而发展为糖尿病、痛风或代谢综合征，尽管血压降低相当，但个体长期结局不同。药物基因组学为基于基因组成的个体化治疗提供了临床潜力。我们提出遗传变异在抗高血压药物的作用中起着重要作用，包括它们的降压作用、不良代谢作用以及它们对临床结果的影响。我们的总体目标是发现、复制和定义两种常用处方类降压药（噻嗪类利尿剂和β-受体阻滞剂）的降压反应、不良代谢反应和长期临床结局（死亡、中风、心脏病发作、糖尿病）的遗传决定因素的机制基础。我们的方法还将深入了解我们在一类药物中研究的遗传关联的一致性（即药物类效应）。 具体目标1和2）使用PEARI数据，发现噻嗪类利尿剂和β 1选择性阻断剂的抗高血压和不良代谢反应（葡萄糖、甘油三酯、尿酸）的遗传决定因素。我们将通过已建立的国际合作，在各种噻嗪类和β受体阻滞剂治疗的队列中复制研究结果。此外，我们将进行一项400例受试者的美托洛尔和氯噻酮随机交叉研究，以进行额外的重复研究，并建立遗传相关性的类效应。具体目的3和4）使用INVEST-GENES临床试验队列，确定使用β-受体阻滞剂+噻嗪治疗预防死亡、心脏病发作、中风和新发糖尿病的遗传预测因子，然后在阿斯科特临床试验遗传队列中进行复制。具体目标5）为目标1-4的发现定义功能多态性及其机制基础。特别是：5A。对从临床反应表型极端取样的个体中的感兴趣的基因组区域进行重测序，和5 b.研究差异基因表达的因果机制，使用各种复杂的分子遗传学实验方法。这项工作的发现可能会导致基因型指导选择抗高血压药物。 公共卫生相关性： 高血压（HTN）影响约7500万美国人，或三分之一的成年人。许多有效的药物可用于治疗HTN，但个体反应不同。我们将研究遗传因素影响血压降低，不良代谢反应，糖尿病的长期风险和预防不良心血管疾病的结果，如心脏病发作和中风的两个常用的药物类别，β-受体阻滞剂和噻嗪类利尿剂在未来的遗传信息可能会被用来指导个体患者的药物治疗的选择。

DESCRIPTION (provided by applicant): Hypertension (HTN) places over 70 million Americans (and approximately one billion individuals worldwide) at substantially increased risk for stroke, heart attack, renal failure, and heart failure, and is the most common chronic disease for which medications are prescribed. There are numerous acceptable first line treatment options for HTN, yet selection of a specific drug for a given patient is empiric, only about 50% of patients have acceptable blood pressure (BP) lowering with a given antihypertensive drug, some experience adverse metabolic effects and develop diabetes, gout or metabolic syndrome as a result of their therapy, and individual long-term outcomes vary despite equivalent BP lowering. Pharmacogenomics offers the clinical potential for individualized therapy based on genetic make-up. We propose genetic variability plays an important role in the effects of antihypertensive drugs, including their BP lowering, adverse metabolic effects, and their influence on clinical outcomes. Our overall aims are to discover, replicate and define the mechanistic basis for genetic determinants of the BP lowering responses, adverse metabolic responses and long-term clinical outcomes (death, stroke, heart attack, diabetes) to two commonly prescribed classes of antihypertensive drugs, thiazide diuretics and p-blockers. Our approach will also provide insight into the consistency of genetic associations we study across drugs within a class (i.e. the drug class effect). Specific Aims 1 and 2) Using PEARI data, discover genetic determinants of antihypertensive and adverse metabolic responses (glucose, triglycerides, uric acid) to thiazide diuretics and (31-selective blockers. We will replicate findings in variety of thiazide and p-blocker-treated cohorts through established international collaborations. Additionally we will conduct a 400 subject randomized crossover study of metoprolol and chlorthalidone for additional replication and to establish a class effect for the genetic associations. Specific Aims 3 and 4) Using the INVEST-GENES clinical trial cohort, identify genetic predictors for prevention of death, heart attack, stroke and new-onset diabetes with p-blocker+thiazide therapy, followed by replication in the ASCOT clinical trial genetic cohort. Specific Aim 5) Define functional polymorphisms and their mechanistic basis for Aim 1-4 discoveries. Specifically: 5a. Resequence genomic regions of interest in individuals sampled from the clinical response phenotype extremes, and 5b. Investigate causal mechanisms for differential gene expression, using a variety of sophisticated molecular genetic experimental approaches. Discoveries from this work could lead to genotype-guided selection of antihypertensive drugs. PUBLIC HEALTH RELEVANCE: Hypertension (HTN) affects about 75 million Americans, or 1 in 3 adults. Many effective drugs are available to treat HTN, but individual responses vary. We will study genetic factors that influence BP lowering, adverse metabolic responses, long-term risk for diabetes and prevention of adverse cardiovascular outcomes like heart attack and stroke for two commonly used drug classes, p-blockers and thiazide diuretics In the future genetic information might be used to guide selection of drug therapy for individual patients.