GENETIC SUSCEPTIBILITY TO LIPID-LOWERING DRUG-INDUCED MYOPATHIES

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）的患者会出现肌肉症状，0.1 - 0.2%（1.9万）的患者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，包括潜在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耐受患者的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）。mccardle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16倍和10倍。50%的患者在肌肉中发现能量代谢缺陷。Aim 1将扩大他汀类肌病患者（560例严重病例；295例轻度病例）的候选疾病和突变的数量，与他汀耐受个体（n = 400）、非他汀类肌病患者（n = 640）和未接触他汀类药物的普通人群（n = 300）进行病例对照比较。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）将被纳入研究，以验证他汀类药物治疗会增加肌肉症状风险的假设。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，确定和描述单核苷酸多态性与他汀类药物肌病之间的临床显著关联。初步研究发现，在肌肉和中枢神经系统组织中存在一个高度相关的缺口样基因（与联合对照组相比p<0.001），并预测在肌肉再生的调节特性中起作用。提出了对预测蛋白的表达研究。其他的基因变异将使用相同的策略来识别。对力、效应大小和连锁不平衡模式的统计分析将是验证我们研究结果的核心。三分之二的严重他汀类药物肌病患者在治疗后有持续的，在某些情况下，逐渐丧失行为能力的长期症状。通过适当识别遗传风险因素、监测药物剂量和定期血液检测肌肉损伤指标，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，不仅是为了降低胆固醇，而且是为了其他与健康相关的应用，确定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，降低与不良后果相关的医疗保健成本，并增加对他汀类药物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以降低血胆固醇而出现严重肌肉症状的患者在治疗后长期存在，在某些情况下，逐渐丧失行为能力的症状。通过适当识别遗传风险因素、监测药物剂量和定期血液检测肌肉损伤指标，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，不仅是为了降低胆固醇，而且是为了其他与健康相关的应用，确定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，降低与不良后果相关的医疗保健成本。

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.