Pharmacogenomic Evaluation of Antihypertensive Responses

描述(由申请人提供)： 高血压(HTN)使7000多万美国人(全球约10亿人)中风、心脏病发作、肾功能衰竭和心力衰竭的风险大幅增加，是最常见的开药治疗的慢性疾病。HTN有许多可接受的一线治疗方案，但针对特定患者的特定药物的选择是经验性的，只有约50%的患者在特定的抗高血压药物治疗后血压(BP)可接受降低，一些患者因其治疗而出现不良代谢影响并发展为糖尿病、痛风或代谢综合征，尽管降压效果相当，但个体的长期结果有所不同。药物基因组学为基于基因构成的个体化治疗提供了临床潜力。我们认为遗传变异在抗高血压药物的作用中起着重要的作用，包括降压、不良代谢作用以及对临床结果的影响。我们的总体目标是发现、复制和确定两种常用的抗高血压药物(噻嗪利尿剂和p-受体阻滞剂)的降压反应、不良代谢反应和长期临床结果(死亡、中风、心脏病发作、糖尿病)的遗传决定因素的机制基础。我们的方法还将提供对我们在一个类别内跨药物研究的遗传关联的一致性的洞察(即药物类别效应)。具体目标1和2)利用PEARI数据，发现抗高血压和对噻嗪利尿剂和(31-选择性阻滞剂)的不良代谢反应(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，在各种噻嗪和β-受体阻滞剂治疗的队列中复制研究结果。此外，我们还将对美托洛尔和氯替利酮进行400名受试者的随机交叉研究，以进行额外的重复试验，并建立遗传关联的类别效应。具体目标3和4)使用Invest-Genees临床试验队列，确定P-受体阻滞剂+噻嗪疗法预防死亡、心脏病发作、中风和新发糖尿病的基因预测因子，然后在ASCOT临床试验基因队列中复制。特定目标5)为目标1-4的发现定义功能多态及其机制基础。具体来说：5A。对来自临床反应表型极端的个体的感兴趣的基因组区域进行重新排序，以及5b。使用各种复杂的分子遗传学实验方法，研究差异基因表达的原因机制。这项工作的发现可能会导致抗高血压药物的基因指导选择。 公共卫生相关性： 高血压(HTN)影响着大约7500万美国人，或者说三分之一的成年人。有许多有效的药物可用于治疗HTN，但个体反应各不相同。我们将研究影响降压的遗传因素、不良代谢反应、糖尿病的长期风险以及预防心脏病发作和中风等不良心血管后果的两类常用药物，p-受体阻滞剂和噻嗪类利尿剂未来可能被用来指导个别患者的药物治疗选择。

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.