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: 8235971
• 负责人: Georgirene Vladutiu
• 金额: $ 39.3万
• 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 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8235971
• 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; 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 effective; cost effectiveness; dosage; drug metabolism; enzyme deficiency; genetic risk factor; genetic variant; genome wide association study; muscle metabolism; muscle regeneration; mutant; notch protein; research study

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. 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.

他汀类药物的益处在降低冠心病的风险和 冠状动脉粥样硬化然而，相关并发症可能危及生命。超过1900万 美国人服用他汀类药物。高达7%（> 130万）会出现肌肉症状，0.1%至0.2% （> 19，000）可能会发生危及生命的肌病。我们的长期目标是找出有临床意义的 与他汀类药物肌病相关的遗传变异，这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， 潜在的遗传性肌肉疾病的患病率以及广泛遗传性肌肉疾病的基因中的遗传变异， 在细胞代谢和结构中的调节作用。这一假设是基于以下研究的初步发现 他汀类药物患者中导致3种常见代谢性肌病的突变等位基因显著增加 肌病与他汀类药物耐受患者（p=0.04）。突变等位基因频率增加高达16倍和10倍 分别存在McArdle病和肉毒碱棕榈酰转移酶II缺乏症。能量缺陷 50%的患者在肌肉中发现代谢。目标1将扩大候选疾病的数量， 在一项病例对照研究中，在他汀类肌病患者（560例重度病例; 295例轻度病例）中评估了突变 与他汀类药物耐受个体（n = 400）、非他汀类药物肌病患者（n = 640）和 一般人群中未暴露于他汀类药物的个体（n = 300）。携带者或 受已知代谢性肌病影响并服用他汀类药物的患者（n = 100）将被纳入，以检验以下假设： 他们在接受他汀类药物治疗时出现肌肉症状的风险会增加。目标2将确定和描述 单核苷酸多态性与他汀类肌病之间的临床显著关联- 使用微阵列分析对合并的DNA样品进行对照全基因组关联研究。初步研究 已经鉴定了一种定位于肌肉中的高度相关的Notch样基因（与联合对照组相比p<0.001） 和CNS组织，并预测在肌肉再生的调节特性中具有作用。表达 对预测的蛋白质进行了研究。其他遗传变异将使用相同的 战略统计分析的权力，影响大小和模式的连锁不平衡将是核心， 验证我们的发现三分之二的严重他汀类肌病患者持续存在， 在某些情况下，治疗后长时间出现渐进性失能症状。这些结果中的许多 通过适当识别遗传风险因素，监测药物剂量， 血液测试肌肉损伤的指标。随着这些重要药物的使用越来越多， 降低胆固醇的目标，但对于其他健康相关的应用，潜在的遗传 风险因素将导致具有成本效益的筛查，降低发病率，降低与不良反应相关的医疗费用， 结果，并增加对他汀类肌病的药物基因组学的理解。许多因他汀类药物治疗降低血胆固醇而出现严重肌肉症状的患者， 并且在某些情况下，治疗后长时间的渐进性失能症状。许多这些 通过适当识别遗传风险因素，监测药物剂量， 定期验血检查肌肉损伤的迹象随着这些重要药物的使用越来越多， 不仅对于降低胆固醇的目标，而且对于其他健康相关的应用， 遗传风险因素将导致成本效益的筛查，降低发病率，降低医疗保健费用 与不良后果有关。