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（由应用程序提供）：此申请解决了广泛的挑战领域（04）临床研究和特定挑战主题，04-HL- 113：在短期风险低的人中预防CVD的成本效益试验。 HMG-COA降低脂质的疗法降低了抑制剂（他汀类药物）用于初级预防的抑制剂（他汀类药物）目前仅在具有多种危险因素或低密度脂蛋白胆固醇升高的老年人中表明。然而，血管内超声研究表明，30年代的大多数健康个体都有早期的冠状动脉粥样硬化迹象。这一令人震惊的事实提高了我们在开始降低脂质疗法以进行所谓初级预防之前延迟太久的可能性。但是，在相对年轻的年轻人中进行他汀类药物治疗的临床试验，表面上健康的个体将是一项艰巨的任务，因为必要的试验样本量将被禁止大，绝对风险降低适度，因此有效性和安全性之间的净平衡和可疑性之间的净平衡。但是，最近，我们和其他人已经验证了许多常见的遗传变异（9p21和其他）与冠状动脉疾病（CHD），血脂异常以及2型糖尿病的发展相关的可重复性，并且这些变体可以用于预测独立于传统风险因素的风险。这些数据表明，遗传变异可能会使个体将个体分为临床因素可以做的事情，并扩大表明基因分型可以允许鉴定治疗可能对动脉粥样硬化心脏病并发症的发展产生显着影响的个体。此外，在多项研究中，特定遗传变异的载体（例如APOE€4，KIF6 719ARG和较短的端粒长度）享有37-67％的汀类药物疗法的相对风险降低相对风险的相对风险降低，而非携带者只有6-34％的相对风险降低了6-34％。同样，也已经鉴定出与他汀类药物治疗的安全性有关（例如SLCO1B1和肌病）的遗传变异。因此，我们假设遗传风险分层可用于识别汀类药物治疗和将对不良反应的风险较低的个体享有更大临床益处的个体。对这种个性化医学方法的验证将为发起量身定制的试验铺平道路，该试验对年轻人至中年人的汀类药物益处，这些人目前无资格参加他汀类药物疗法。这是该应用程序的总体目标是测试一组遗传变异的能力，以预测他汀类药物治疗的益处和风险。在AIM 1中，我们将测试使用汀类药物治疗的患者是否使用来自5项汀类药物治疗临床试验的40,000多名受试者的数据来确定在他汀类药物治疗方面具有更大临床益处的患者。在AIM 2中，我们将测试特定的遗传变异板是否识别出在同一同胞中他汀类药物引起的不良反应风险更高的患者。汀类药物的治疗通常直到一个人患有明显的心脏病或年龄较大并且具有多种传统危险因素才能处方。但是，在30多岁的大多数个体中可以找到冠状动脉疾病的证据。我们认为，通过检查多个基因，我们可以确定那些将从他汀类药物疗法中获得更大好处的人和将对不良反应的风险较低的人。对此类信息的验证将为他在当前不具备他汀类药物疗法的年轻人至中年人中对他汀类药物疗法的临床益处的经济，可行和安全试验铺平道路。