Pharmacogenetics of Post-ACS Therapy

ACS 后治疗的药物遗传学

基本信息

批准号：
7785983
负责人：
HOWARD L MCLEOD
金额：
$ 44.49万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-01-01 至 2009-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7785983
关键词：
Acute Address Adrenergic Antagonists Adrenergic Receptor Adrenergic beta-Antagonists Angiotensin-Converting Enzyme Inhibitors Antibiotics Area Autoimmune Diseases Cardiac Cardiovascular Diseases Cardiovascular system Characteristics Cholesterol Clinical Comorbidity Complex Constitution Coronary Data Decision Making Development Diabetes Mellitus Disease Dose Enzymes Event Functional disorder Genes Genetic Genetic Status Genomics Genotype Guidelines Heart Heart Transplantation Hospitals Human Individual Left Medical Metabolic Metabolic Diseases Metabolism Morbidity - disease rate Myocardial Outcome PPAR alpha PPAR gamma Patients Peptidyl-Dipeptidase A Peroxisome Proliferator-Activated Receptors Pharmaceutical Preparations Pharmacogenetics Pharmacotherapy Phenotype Physicians Plasma Prospective Studies Publishing Receptor Gene Research Research Personnel Rheumatism Risk Role Secondary Prevention Single Nucleotide Polymorphism Sodium Channel Symptoms Therapeutic Thiopurine Methyltransferase Deficiency Toxic effect Translations Ventricular Western World acute coronary syndrome base beta-adrenergic receptor cellular targeting clinical practice diabetes risk diabetic evidence base gene environment interaction genetic variant heart metabolism improved molecular imaging mortality prevent prognostic prospective thiopurine thiopurine methyltransferase tool

项目摘要

Acute Coronary Syndrome (ACS) is a major cause of morbidity and mortality in the Western World. Multiple patient characteristics, including genetic constitution and metabolic status (in particular diabetes), have significant influence on patient outcome. The last decade has seen major advances in post-ACS treatment, including the administration of beta adrenergic receptor antagonists (beta blockers; BB) and angiotensin converting enzyme (ACE) inhibitors to prevent post-ACS complications. The avaiiabiiity of multiple therapeutic options with clear benefit post-ACS requires that clinical decisions must be made for individual patients. However, there are currently insufficient tools to guide the selection of post-ACS therapy in an objective and evidenced-based manner. The expansion of human genomic information has led to exciting new opportunities for the application of pharmacogenetics to improve the selection of post-ACS therapy. There is a growing list of published examples where a genetic variant in the metabolism, transport, or cellular target of a drug is clearly associated with patient toxicity or clinical outcome. The greatest obstacle to the integration of pharmacogenetics into clinical practice is the paucity of quantitative data on the predictive ability of genetics in the selection of drug therapy. Accordingly, we seek to address the need for quantitative assessment of the predictive impact of relevant genetic variants in the context of modern post-ACS therapy. Recent findings by investigators of this SCCOR proposal and others implicate genes of the PPAR gene regulatory complex as candidate modifiers of metabolic and cardiovascular disease states. This project will address the following Specific Aims: 1) To determine if a homozygous SNP genotype in PPAR complex genes (PPARalpha, PPARgamma, PGC1alpha) involved in cardiac metabolism will predict improved efficacy of ACE-I or BB therapy in preventing MACE or improving symptom score in patients with ACS; 2) To perform gene-environment interaction analyses to ascertain the impact of diabetes on the predictive power of PPAR complex genes for improved efficacy of ACE-I or BB therapy in preventing MACE or improving symptom score in patients with ACS; and 3) To develop a polygenic panel of SNPs in multiple genes regulating myocardial metabolism to predict improved efficacy of ACE-I or BB in preventing MACE or improving symptom score among patients with ACS. These aims provide a comprehensive framework for our strategy to generate prospective information on the predictive power of metabolic genes on the selection of therapy for ACS. The resulting tools will allow for more precise selection of post-ACS therapy for individual patients.

急性冠状动脉综合征（ACS）是西方世界发病和死亡的主要原因。多种患者特征，包括遗传体质和代谢状态（特别是糖尿病），对患者的治疗结果有重大影响。过去十年，ACS 后治疗取得了重大进展，包括使用 β 肾上腺素能受体拮抗剂（β 受体阻滞剂；BB）和血管紧张素转换酶 (ACE) 抑制剂来预防 ACS 后并发症。 ACS 后具有明显益处的多种治疗方案的可用性要求必须针对个体患者做出临床决策。然而，目前还没有足够的工具来客观、循证地指导 ACS 后治疗的选择。人类基因组信息的扩展为应用药物遗传学来改善 ACS 后治疗的选择带来了令人兴奋的新机会。越来越多的已发表例子表明，药物代谢、转运或细胞靶标中的遗传变异与患者毒性或临床结果明显相关。将药物遗传学融入临床实践的最大障碍是缺乏关于遗传学在药物治疗选择中的预测能力的定量数据。因此，我们寻求满足对相关遗传变异在现代 ACS 治疗背景下的预测影响。 SCCOR 提案和其他提案的研究人员最近的发现表明 PPAR 基因调控复合物的基因是代谢和心血管疾病状态的候选调节剂。该项目将解决以下具体目标： 1) 确定 PPAR 复合体基因（PPARα、PPARγ、PGC1α）中的纯合 SNP 基因型是否参与心脏疾病代谢将预测 ACE-I 或 BB 疗法在预防 MACE 或改善 ACS 患者症状评分方面的功效提高； 2) 进行基因-环境相互作用分析，以确定糖尿病对 PPAR 复合体基因预测能力的影响，从而提高 ACE-I 或 BB 疗法预防 MACE 或改善 ACS 患者症状评分的功效； 3) 开发多个基因中的 SNP 多基因组调节心肌代谢以预测 ACE-I 或 BB 在预防 MACE 或改善 ACS 患者症状评分方面的功效改善。这些目标为我们的策略提供了一个全面的框架，以生成有关代谢基因对 ACS 治疗选择的预测能力的前瞻性信息。由此产生的工具将允许为个体患者更精确地选择 ACS 后治疗。