Pharmacogenetic Response to Naltrexone for Alcohol Dependence

我们中心的证据表明，MU-阿片受体(OPRM1)的一个功能多态性可能是 与阿片类拮抗剂纳曲酮(NTX)治疗酒精的临床反应相关 依赖。该多态性是外显子1(Asn40Asp)上的单核苷酸多态性(SNP)。苏格兰民族党 几乎只在欧洲或亚洲血统的人中发现，并已在体外证明 并在体内改变受体的功能。在对NTX依从者的回顾分析中， 用一个或两个副本的Asp40变异体有73.9%的应答(不再酗酒)； 携带Asn40等位基因纯合子的受试者对治疗的阳性反应率仅为49.0%(p=0.040)。在……里面 接受安慰剂治疗的患者的反应与基因型之间没有关联。这一发现是 最近在联合研究的初步回顾分析中证实，患者的应答率为87% 与完成试验的Asp40等位基因。虽然肯定不是决定性的，但这些数据表明了 通过处理交互作用，可以更好地定义处理算法，并消除以下信念 上瘾不是一种疾病。在与FDA的讨论中，一项预期的随机安慰剂对照试验是 需要考虑更改标签或批准生物标记物。 这项建议的主要目的是研究Asp40等位基因变异和阿片类药物之间的相互作用。 受体拮抗。我们提出了一项关于NTX和安慰剂的前瞻性、为期12周的双盲随机试验 在酒依赖患者中，具有一个或两个副本的Asp40多态与 Asn40等位基因纯合。受试者将根据基因(2x2细胞)随机接受药物治疗 设计)。主要结果将是治疗反应。结果证实了与临床的联系 回应可能会大大促进NTX的使用，并将导致更好地理解 酒精依赖的病理生理学。所有受试者基因分型的前瞻性设计和纳入 将允许对其他可能的候选基因的次要假设进行测试，并且获得的样本将 促进治疗反应的全基因组联合研究，使用 奖赏系统的药理学探索。项目叙事 酒精依赖是全世界导致残疾的主要原因之一。这 应用程序侧重于识别对 纳曲酮治疗。识别对治疗有反应的患者是至关重要的 改善公共卫生议程以减轻疾病负担

Evidence from our center suggests that a functional polymorphism of the mu-opioid receptor (OPRM1) may be associated with clinical response to the opioid antagonist, naltrexone (NTX) in the treatment of alcohol dependence. The polymorphism is a single nucleotide polymorphism (SNP) in exon 1 (Asn40Asp). The SNP is found almost exclusively in individuals of European or Asian descent and has been demonstrated in vitro and in vivo to alter the function of the receptor. In retrospective analyses of patients adherent to NTX, persons with one or two copies of the Asp40 variant had a 73.9 % response (no relapse to alcohol use); whereas subjects homozygous for the Asn40 allele only had a 49.0 % positive response rate to treatment (p=0.040). In patients receiving placebo there was no association between response and genotype. This finding was recently confirmed in preliminary retrospective analysis of the COMBINE study with a 87% response in patients with the Asp40 allele who completed the trial. While certainly not definitive, these data suggest the potential for a genotype by treatment interaction that could better define treatment algorithms and dispel the belief that addiction is not a disease. In discussions with the FDA, a prospective randomized placebo controlled trial is required to consider labeling changes or approval of a biomarker. The primary aim of this proposal is to examine the interaction between the Asp40 allele variant and opioid receptor antagonism. We propose a prospective, 12-week, double-blind randomized trial of NTX and placebo among alcohol dependent patients with one or two copies of the Asp40 polymorphism compared to those homozygous for the Asn40 allele. Subjects will be randomized to medication based on genotype (2X2 cell design). The primary outcome will be treatment response. Results confirming the association with clinical response may significantly advance the use of NTX and will lead to a better understanding of the pathophysiology of alcohol dependence. The prospective design and inclusion of genotyping of all subjects will allow secondary hypotheses to be tested for other possible candidate genes and the acquired sample will facilitate whole genome associate studies of treatment response in a well characterized sample using a pharmacological probe of the reward system. Project Narrative Alcohol dependence is one of the leading causes of disability worldwide. This application focuses on identification of patients who are particularly responsive to treatment with naltrexone. Identification of patients responsive to treatment is vital to improving the public health agenda for reducing burden of illness