GENETIC SUSCEPTIBILITY TO LIPID-LOWERING DRUG-INDUCED MYOPATHIES

他汀类药物在降低冠心病风险和延缓高血压进展方面的益处是毋庸置疑的。 冠状动脉粥样硬化。然而，相关的并发症可能会危及生命。1900多万 美国人服用他汀类药物。高达7%(&gt；130万)会出现肌肉症状，0.1%至0.2% (&gt；19,000)可能会患上危及生命的肌病。我们的长期目标是确定有临床意义的 基因变异与他汀类肌病相关，这是一种病因多样的复杂疾病。我们的假设是 他汀类肌病易感性的遗传结构是复杂的，并将包括 遗传性肌肉疾病的患病率以及广谱基因的遗传变异 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 分别为McArdle病和肉碱棕榈酰转移酶II缺乏症。能源方面的缺陷 50%的患者在肌肉中发现了代谢。目标1将扩大候选障碍的数量，并 他汀类肌病患者基因突变的病例对照研究(560例重症患者；295例轻度患者) 与他汀类药物耐受者(n=400)、非他汀类肌病患者(n=640)和 普通人群中未接触他汀类药物的个体(n=300)。携带或携带病毒的个人 受已知代谢性肌病影响并服用他汀类药物(n=100)的患者将被纳入，以检验这一假设 在接受他汀类药物治疗时，他们出现肌肉症状的风险将会增加。目标2将确定和描述 单核苷酸多态与他汀类肌病的临床显著相关性 使用微阵列分析对汇集的DNA样本进行全基因组关联研究。初步研究 在肌肉中发现了一个高度相关的缺口样基因(P&lt；0.001与联合控制组) 和中枢神经系统组织，并被预测在肌肉再生的调节特性中起作用。表达式 对预测的蛋白质提出了研究建议。更多的遗传变异将使用相同的 策略。对功率、影响大小和连锁不平衡模式的统计分析将是 验证我们的发现。三分之二患有严重他汀类肌病的患者有持续性和 部分病例出现持续时间较长的进行性丧失行为能力症状。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，并定期 血液检测肌肉损伤的指标。随着这些重要药物的使用越来越多，不仅是为了 降低胆固醇的目标，但对于其他与健康相关的应用，识别潜在的遗传性 风险因素将导致具有成本效益的筛查，降低发病率，降低与不利因素相关的医疗成本 结果，并增加了对他汀类肌病药物基因组学的理解。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，都有持续性 在某些情况下，长期治疗后会出现渐进性丧失能力的症状。其中许多 通过适当识别遗传风险因素、监测药物剂量、 并定期进行血液测试，以确定肌肉损伤的指标。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，并降低医疗成本 与不良后果相关。

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.