GENETIC SUSCEPTIBILITY TO LIPID-LOWERING DRUG-INDUCED MYOPATHIES

对降脂药物引起的肌病的遗传易感性

• 批准号: 7807183
• 负责人: Georgirene Vladutiu
• 金额: $ 40.46万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT BUFFALO
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-05-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7807183
• 关键词: Adverse effects; Affect; Alleles; Anesthesia procedures; Architecture; Attention; Biochemical; Biopsy; Blood; Blood Tests; Candidate Disease Gene; Carnitine Palmitoyltransferase II; Case-Control Studies; Cell physiology; Cholesterol; Complex; Control Groups; Coronary Arteriosclerosis; Coronary heart disease; DNA; Defect; Diagnosis; Disease; Disease Progression; Drug Monitoring; Energy Metabolism; Energy Metabolism Pathway; Etiology; Exercise; Fasting; Future; Gene Frequency; Gene Mutation; Gene-Modified; General Population; Generations; Genes; Genetic; Genetic Predisposition to Disease; Genetic Variation; Glycogen Storage Disease Type V; Goals; Health Care Costs; Individual; Inherited; Lead; Life; Linkage Disequilibrium; Lipids; Maps; Measurable; Metabolic; Metabolic stress; Metabolism; Microarray Analysis; Morbidity - disease rate; Muscle; Mutation; Myopathy; Outcome; Patients; Pattern; Pharmaceutical Preparations; Pharmacogenomics; Predisposition; Prevalence; Property; Proteins; Rhabdomyolysis; Risk; Risk Factors; Role; Sampling; Screening procedure; Secondary to; Severities; Single Nucleotide Polymorphism; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Structure; Symptoms; Testing; Tissues; Validation; Variant; adverse outcome; base; case control; clinically significant; cost; cost effectiveness; dosage; drug metabolism; enzyme deficiency; genetic risk factor; genetic variant; genome wide association study; muscle regeneration; mutant; notch protein; public health relevance; research study

DESCRIPTION (provided by applicant): The benefits of statins are undisputed in reducing the risk of coronary heart disease and the progression of coronary atherosclerosis. Nevertheless, associated complications can be life-threatening. More than 19 million people in the U.S. take statins. Up to 7% (>1.3 million) will develop muscle symptoms and 0.1 to 0.2% (>19,000) may develop life-threatening myopathies. Our long-term goal is to identify clinically significant genetic variants associated with statin myopathy, a complex disorder with diverse etiologies. Our hypothesis is that the genetic architecture of susceptibility to statin myopathy is complex and will include an increased prevalence of underlying hereditary muscle disorders as well as genetic variation in genes with broad regulatory roles in cellular metabolism and structure. This hypothesis is based on preliminary findings of significantly increased mutant alleles causative for 3 common metabolic myopathies in patients with statin myopathy vs. statin-tolerant patients (p=0.04). Up to 16- and 10-fold increases in mutant allele frequencies exist for McArdle disease and carnitine palmitoyltransferase II deficiency, respectively. Defects in energy metabolism were found in muscle in 50% of patients. Aim 1 will expand the number of candidate disorders and mutations evaluated in patients with statin myopathies (560 severe cases; 295 mild cases) in a case-control comparison with statin-tolerant individuals (n = 400), patients with non-statin myopathies (n = 640), and individuals in the general population not exposed to statins (n = 300). Individuals who are carriers for or affected with known metabolic myopathies and take statins (n = 100) will be included to test the hypothesis that they will be at increased risk for muscle symptoms while on statin therapy. Aim 2 will identify and characterize clinically significant associations between single nucleotide polymorphisms and statin myopathies in a case- control genome-wide association study of pooled DNA samples using microarray analysis. Preliminary studies have identified a highly associated notch-like gene (p<0.001 vs. combined control groups) localized in muscle and CNS tissue and predicted to have a role in regulatory properties of muscle regeneration. Expression studies are proposed for the predicted protein. Additional genetic variants will be identified using the same strategy. Statistical analyses for power, effect size and patterns of linkage disequilibrium will be central to the validation of our findings. Two-thirds of patients referred with severe statin myopathies have persistent and, in some cases, progressively incapacitating symptoms of long duration post-therapy. Many of these outcomes will be preventable with appropriate identification of genetic risk factors, monitoring of drug dosage, and regular blood testing for indicators of muscle damage. With the increasing use of these important drugs, not only for cholesterol-lowering goals but for other health-related applications, the identification of underlying hereditary risk factors will lead to cost-effective screening, reduced morbidity, lower health care costs relevant to adverse outcomes, and increased understanding of the pharmacogenomics of statin myopathies. PUBLIC HEALTH RELEVANCE. Many patients with severe muscle symptoms from statin therapy to lower blood cholesterol have persistent and, in some cases, progressively incapacitating symptoms of long duration post-therapy. Many of these outcomes will be preventable with appropriate identification of genetic risk factors, monitoring of drug dosage, and regular blood testing for indicators of muscle damage. With the increasing use of these important drugs, not only for cholesterol-lowering goals but for other health-related applications, the identification of underlying hereditary risk factors will lead to cost-effective screening, reduced morbidity, and lower health care costs relevant to adverse outcomes.

描述(由申请人提供)：他汀类药物在降低冠心病风险和冠状动脉粥样硬化进展方面的益处是毋庸置疑的。然而，相关的并发症可能会危及生命。美国有1900多万人服用他汀类药物。多达7%(&gt；130万)会出现肌肉症状，0.1%到0.2%(&gt；19000)可能会发展成危及生命的肌病。我们的长期目标是确定与他汀类肌病相关的临床上有意义的基因变异，他汀类肌病是一种具有多种病因的复杂疾病。我们的假设是，他汀类肌病易感性的遗传结构是复杂的，将包括潜在遗传性肌肉疾病的发病率增加，以及在细胞代谢和结构中具有广泛调节作用的基因的遗传变异。这一假设是基于与他汀类药物耐受患者相比，他汀类肌病患者中导致3种常见代谢性肌病的突变等位基因显著增加的初步发现(p=0.04)。McArdle病和肉碱棕榈酰转移酶II缺乏症的突变等位基因频率分别增加了16倍和10倍。50%的患者存在肌肉能量代谢缺陷。目的1通过与他汀类药物耐受个体(400例)、非他汀类肌病患者(640例)和普通人群中未接触他汀类药物的个体(300例)进行病例对照研究，扩大他汀类肌病患者(560例重症患者，295例轻度患者)的候选疾病和突变的数量。已知的代谢性肌病携带者或受其影响并服用他汀类药物(n=100)的个人将被包括在内，以测试他们在接受他汀类药物治疗时肌肉症状风险增加的假设。目的2将在使用微阵列分析的混合DNA样本的病例对照全基因组关联研究中，识别和表征单核苷酸多态与他汀类肌病之间的临床显著关联。初步研究已经确定了一个高度相关的缺口样基因(P&lt；0.001与联合对照组)，定位于肌肉和中枢神经系统组织，并被预测在肌肉再生的调节特性中发挥作用。建议对预测的蛋白质进行表达研究。将使用相同的策略识别更多的遗传变异。对连锁不平衡的力量、效应大小和模式的统计分析将是验证我们的发现的核心。三分之二的严重他汀类肌病患者在治疗后有持续性的，在某些情况下，逐渐丧失能力的症状。如果适当识别遗传风险因素，监测药物剂量，并定期进行肌肉损伤指标的血液检测，这些结果中的许多都是可以预防的。随着这些重要药物的使用越来越多，不仅用于降胆固醇目标，而且用于其他与健康相关的应用，识别潜在的遗传风险因素将导致具有成本效益的筛查，减少发病率，降低与不良结果相关的医疗成本，并增加对他汀类肌病药物基因组学的了解。与公共卫生相关。许多有严重肌肉症状的患者，从他汀类药物治疗到降低血胆固醇，都会在治疗后出现持续的、在某些情况下逐渐丧失能力的症状。如果适当识别遗传风险因素，监测药物剂量，并定期进行肌肉损伤指标的血液检测，这些结果中的许多都是可以预防的。随着这些重要药物的使用越来越多，不仅用于降胆固醇目标，而且用于其他与健康相关的应用，识别潜在的遗传风险因素将导致具有成本效益的筛查，减少发病率，并降低与不良结果相关的医疗保健成本。