COMBINE genetics study: The pharmacogenetics of alcoholism treatment response: Genes and mechanisms
COMBINE genetics study: The pharmacogenetics of alcoholism treatment response: Genes and mechanisms
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DOI：
10.15288/jsas.2005.s15.56
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发表时间：
2005-07-01
期刊：
影响因子：
--
通讯作者：
Anton, R
中科院分区：
文献类型：
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作者：
Goldman, D;Oroszi, G;Anton, R
目的：治疗的部分疗效和个体间不良事件的差异是酒精中毒治疗的挑战和机遇。个体化治疗和理解差异治疗反应的起源可能需要鉴定基因的遗传功能变体。奖励、执行认知功能、焦虑和烦躁的神经生物学已被确定为可能具有可预测治疗反应的遗传基础的关键领域。方法：联合收割机研究提供了一个独特的机会来评估影响成瘾和长期戒断的神经生物学中心的特定遗传基因座（标记物）。该研究还讨论了药物代谢和作用的变化。基于功能性和丰度选择候选遗传标记用于研究。结果如下：COMT Val 158 Met是一种常见的（次要等位基因频率0.42），功能性，儿茶酚胺代谢酶多态性与三倍相关。Val 158 Met改变执行认知功能，压力和焦虑反应以及大脑内源性阿片功能。OPRM 1 Asn 40 Asp是μ-阿片受体的一种常见（次要等位基因频率0.10）功能多态性，其可作为纳洛酮作用中的看门分子，最近报道可影响纳洛酮反应。HTTLPR（次要等位基因频率0.40）改变5-羟色胺转运蛋白功能，影响焦虑、烦躁和强迫行为，这些在联合收割机中评估，可能与复发和成瘾行为有关。结论：所有基因检测都是通过单独的人类研究方案获得同意的，并且该检测是非临床的、保密的，并且与临床记录分开进行，以保护自愿参加联合收割机这方面的人类研究参与者。
Objective: Partial efficacy of treatment and differences in adverse events across individuals are a challenge and an opportunity in the treatment of alcoholism. Individuation of therapy and understanding origins of differential treatment response may require identification of inherited functional variants of genes. The neurobiology of reward, executive cognitive function, anxiety and dysphoria have been identified as critical domains that may have a genetic basis that could predict treatment response. Method: The COMBINE Study presents a unique opportunity to evaluate specific genetic loci (markers) that affect neurobiology central to addiction and extended withdrawal. The study also addresses variation in drug metabolism and action. Candidate genetic markers are selected for study based on functionality and abundance. Results: COMT Val158Met is a common (minor allele frequency 0.42), functional, catecholamine-metabolizing enzyme polymorphism with threefold relevance. Val158Met alters executive cognitive function, stress and anxiety responses and brain endogenous opioid function. OPRM1 Asn40Asp is a common (minor allele frequency 0.10), functional polymorphism of the mu-opioid receptor, which may serve as a gatekeeper molecule in naltrexone's actions and was recently reported to affect naltrexone response. HTTLPR (minor allele frequency 0.40) alters serotonin transporter function to affect anxiety, dysphoria and obsessional behavior, which are assessed in COMBINE and may be related to relapse and addictive behavior. Conclusions: All genetic testing is consented through a separate human research protocol, and the testing is conducted nonclinically, confidentially and apart from the clinical record to protect human research participants who have volunteered for this aspect of COMBINE.