Genetic Risk Stratification to Identify Individuals for Early Statin Therapy

遗传风险分层以确定早期他汀类药物治疗的个体

• 批准号: 7817823
• 负责人: MARC S SABATINE
• 金额: $ 49.99万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7817823
• 关键词: 9p21; Address; Adverse effects; Adverse event; Adverse reactions; Alleles; Apolipoprotein E; Area; Benefits and Risks; Biological; Cardiovascular system; Cell Aging; Clinical; Clinical Research; Clinical Trials; Coronary; Coronary Arteriosclerosis; Coronary heart disease; DNA; Data; Development; Dyslipidemias; Enrollment; Equilibrium; European; Event; Genes; Genetic Markers; Genetic Polymorphism; Genetic Research; Genetic Risk; Genotype; Goals; Guidelines; Heart Diseases; Hepatic; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Individual; LDL Cholesterol Lipoproteins; Length; Link; Lipids; Measures; Mediating; Medicine; Modeling; Myocardial Infarction; Myopathy; Non-Insulin-Dependent Diabetes Mellitus; Patients; Persons; Plasma; Population; Prevention; Primary Prevention; Qualifying; Randomized Controlled Clinical Trials; Relative (related person); Relative Risks; Reporting; Risk; Risk Factors; Risk Reduction; Safety; Sample Size; Sampling; Simvastatin; Stratification; Testing; Transaminases; Ultrasonography; Validation; Variant; Work; base; cardiovascular risk factor; cell age; cohort; cost; disorder risk; experience; genetic risk factor; genetic variant; high risk; middle age; prevent; response; skeletal; sobriety; telomere; uptake

DESCRIPTION (provided by applicant): This application addresses broad Challenge Area (04) Clinical Research and specific Challenge Topic, 04-HL- 113: Cost-Effective Trials of CVD Prevention in Persons with Low Short-Term Risk. Lipid-lowering therapy with HMG-CoA reductase inhibitors (statins) for primary prevention is currently only indicated in older individuals with multiple risk factors or profoundly elevated low-density lipoprotein cholesterol. Yet intravascular ultrasound studies have revealed that the majority of healthy individuals in their 30's have early signs of coronary atherosclerosis. This sobering fact raises the possibility that we are delaying too long before initiating lipid-lowering therapy for so-called primary prevention. However, conducting a clinical trial of statin therapy in relatively young, ostensibly healthy individuals would be a daunting task as the necessary trial sample size would be prohibitively large, the absolute risk reduction modest, and thus the net balance between efficacy and safety questionable. Recently, though, we and others have validated a number of common genetic variants (9p21 and others) as being reproducibly associated with the risk for coronary heart disease (CHD), dyslipidemia, and the development of type 2 diabetes, and that these variants can be used to predict risk independent of traditional risk factors. These data suggest that genetic variants can risk stratify individuals beyond what clinical factors can do, and, by extension, suggest that genotyping may allow for identification of individuals in whom therapy may have a marked influence on the development of complications of atherosclerotic heart disease. Moreover, across multiple studies, carriers of specific genetic variants (e.g., APOE ¿4, KIF6 719Arg, and shorter telomere length) enjoy 37-67 percent relative risk reductions in major cardiovascular events with statin therapy, whereas non-carriers have only 6-34 percent risk relative risk reductions. Similarly, genetic variants have also been identified that are associated with the safety profile of statin therapy (e.g., SLCO1B1 and myopathy). We therefore hypothesize that genetic risk stratification can be used to identify individuals who enjoy greater clinical benefit from statin therapy and individuals who will be at lower risk for adverse reactions. Validation of this personalized medicine approach would pave the way for launching a tailored trial of the benefit of statin therapy in young to middle-aged individuals who currently would not qualify for statin therapy. Thus, the overall goal of this application is to test the ability of a panel of genetic variants to predict benefits and risks with statin therapy. In Aim 1 we will test whether specific panels of genetic variants identify patients who experience a greater clinical benefit with statin therapy using data from over 40,000 subjects enrolled in 5 clinical trials of statin therapy. In Aim 2 we will test whether specific panels of genetic variants identify patients who experience a higher risk of statin-induced adverse effects in the same cohorts. Treatment with a statin is typically not prescribed until an individual has had overt heart disease or is older and has multiple traditional risk factors; however, evidence of coronary artery disease can be found in a majority of individuals in their 30's. We believe that by examining multiple genes, we can identify individuals who will enjoy a greater benefit from statin therapy and individuals who will be at lower risk for adverse reactions. Validation of such information would pave the way for launching an economical, feasible, and safe trial of the clinical benefit of statin therapy in young to middle-aged individuals who currently do not qualify for statin therapy.

描述（由申请人提供）：本申请涉及广泛的挑战领域 (04) 临床研究和具体挑战主题，04-HL-113：短期低风险降脂疗法预防 CVD 的成本效益试验。 HMG-CoA 还原酶抑制剂（他汀类药物）用于一级预防目前仅适用于具有多种危险因素或低密度脂蛋白胆固醇严重升高的老年人，但血管内超声研究表明。研究表明，大多数 30 多岁的健康个体都有冠状动脉粥样硬化的早期症状，这一发人深省的事实表明，我们在开始进行所谓的一级预防的降脂治疗之前，可能会拖延太久。在相对年轻、表面上健康的个体中进行治疗将是一项艰巨的任务，因为必要的试验样本量将大得令人望而却步，绝对风险降低幅度不大，因此最近，我们和安全性之间的净平衡值得怀疑。其他人已经验证了一些常见的遗传变异（9p21 和其他）与冠心病 (CHD)、血脂异常和 2 型糖尿病的风险可重复相关，并且这些变异可用于预测风险独立性这些数据表明，遗传变异可以对个体进行超出临床因素所能造成的风险分层，并且进一步表明，基因分型可以识别治疗中可能对并发症的发生有显着影响的个体。并发症。此外，多项研究表明，特定遗传变异（例如 APOE ¿）的携带者。 4、KIF6 719Arg 和较短的端粒长度）通过他汀类药物治疗可将主要心血管事件的相对风险降低 37-67%，而非携带者的风险相对风险仅降低 6-34%。与他汀类药物治疗的安全性相关（例如 SLCO1B1 和肌病），因此我们面临着遗传风险分层可用于识别喜欢的个体。他汀类药物治疗具有更大的临床益处，并且不良反应风险较低的个体对这种个性化医疗方法的验证将为在目前不会出现不良反应的年轻至中年个体中启动他汀类药物治疗的益处的定制试验铺平道路。因此，本申请的总体目标是测试一组基因变异预测他汀类药物治疗的益处和风险的能力。在目标 1 中，我们将测试特定的基因变异组是否能够识别经历过他汀类药物治疗的患者。更大的临床效益他汀类药物治疗使用来自 5 项他汀类药物治疗临床试验的超过 40,000 名受试者的数据，在目标 2 中，我们将测试特定的基因变异组是否能识别出在同一队列中经历他汀类药物引起的不良反应风险较高的患者。他汀类药物通常只有在患有明显心脏病或年龄较大且具有多种传统危险因素时才会开出；然而，我们认为大多数 30 多岁的人都可以发现冠状动脉疾病的证据。通过检查多个基因，我们可以识别哪些人将从他汀类药物治疗中获益更大，哪些人发生不良反应的风险较低，这些信息的验证将为启动经济、可行和安全的试验铺平道路。他汀类药物治疗对目前不符合他汀类药物治疗资格的年轻至中年个体的临床益处。