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: 7616204
• 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/7616204
• 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; 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无可争议的。然而，相关并发症可能危及生命。美国有超过1900万人服用他汀类药物。高达7%（> 130万）会出现肌肉症状，0.1%至0.2%（> 19，000）可能会出现危及生命的肌病。我们的长期目标是确定与他汀类肌病相关的临床显著的遗传变异，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，将包括潜在的遗传性肌肉疾病的患病率增加，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。这一假设是基于他汀类肌病患者与他汀类耐受患者相比，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结果（p=0.04）。高达16倍和10倍的突变等位基因频率增加存在麦卡德尔病和肉毒碱棕榈酰转移酶II缺乏症，分别。在50%的患者中发现肌肉能量代谢缺陷。目的1将扩大他汀类肌病患者（560例重度病例; 295例轻度病例）与他汀类药物耐受个体（n = 400）、非他汀类肌病患者（n = 640）和未暴露于他汀类药物的一般人群（n = 300）的病例对照比较中评估的候选疾病和突变数量。将纳入已知代谢性肌病携带者或受其影响并服用他汀类药物的个体（n = 100），以检验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合并DNA样本的病例对照全基因组关联研究中鉴定和表征单核苷酸多态性与他汀类肌病之间的临床显著关联。初步研究已经鉴定了位于肌肉和CNS组织中的高度相关的notch样基因（p<0.001，与组合对照组相比），并且预测其在肌肉再生的调节特性中具有作用。表达研究提出了预测的蛋白质。将使用相同的策略鉴定其他遗传变异。统计分析的权力，效应大小和模式的连锁不平衡将是中央验证我们的研究结果。三分之二的严重他汀类肌病患者在治疗后有持续性，在某些情况下，长期进行性失能症状。通过适当识别遗传风险因素，监测药物剂量以及定期血液检测肌肉损伤指标，这些结果中的许多是可以预防的。随着这些重要药物的使用越来越多，不仅用于降低胆固醇的目标，而且用于其他健康相关的应用，潜在遗传风险因素的识别将导致具有成本效益的筛查，降低发病率，降低与不良结局相关的医疗保健成本，并增加对他汀类肌病的药物基因组学的理解。 公共卫生相关性。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在治疗后长时间出现持续性症状，在某些情况下，出现进行性失能症状。通过适当识别遗传风险因素，监测药物剂量以及定期血液检测肌肉损伤指标，这些结果中的许多是可以预防的。随着这些重要药物的使用越来越多，不仅用于降低胆固醇的目标，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，降低发病率，并降低与不良结果相关的医疗保健成本。