PHARMACOGENOMICS OF ACAMPROSATE TREATMENT OUTCOME

酒精使用障碍（AUD）的经济和健康后果需要有效的治疗 战略布局反应生物标志物的发现有望通过允许 个性化的治疗选择。我们的初步发现表明， 阿坎酸治疗的伴有GRIN 2B基因多态性和血浆谷氨酸变化的酗酒者 程度.我们的神经影像学数据表明左背外侧前额叶的谷氨酸水平 皮质对酒精有渴望，前扣带回中的谷氨酸水平下降，以响应 阿坎酸治疗然而，以前的研究使用了一组有限的候选基因，并且没有包括一个候选基因。 安慰剂对照用于测定阿坎酸特异性作用。此外，还没有研究表明， 评估了基因对清醒的贡献与其他治疗结果。因此，项目1将搜索 在接受治疗的AUD患者中，与阿坎酸与安慰剂治疗反应相关的遗传标志物 在包括接受阿坎酸和安慰剂治疗的酗酒者的合并样本中， 联合收割机、PREDICT和P20 CITA研究以及在社区接受治疗的800名AUD患者的新样本- 在阿坎酸的双盲随机安慰剂对照研究中，这将使我们能够 对全基因组与AUD治疗结局之间的关联进行荟萃分析， 用于酒精中毒研究领域药物基因组学研究的样本（总N>2400）。我们还将 评估由常见多态性解释的遗传力和不同基因的遗传结构， 酒精中毒治疗反应的措施。最后，我们将进行药物代谢组学-和 通过选择候选靶点进行额外分析， 与项目2中阿坎酸反应相关的代谢和成像标志物相关的途径， 3.我们还在项目2中描述的神经元衍生的iPS细胞系中使用功能分析， 验证我们的发现 相关性（参见说明）： 这些研究的完成将为AUD的个体化治疗选择提供证据 患者和指导治疗策略的发展的基础上的生物标志物的反应。

The economic and health consequences of Alcohol Use Disorders (AUDs) call for efficient treatment strategies. The discovery of response biomarkers is expected to improve treatment outcomes by allowing for the personalization of treatment selection. Our preliminary findings indicated an association of sobriety in acamprosate-treated alcoholics with a polymorphism in the GRIN2B gene and changes in plasma glutamate levels. Our neuroimaging data indicate an association of glutamate levels in the left dorsolateral prefrontal cortex with alcohol cravings and decreased glutamate levels in the anterior cingulate in response to acamprosate treatment. Yet, previous studies used a limited set of candidate genes and did not include a placebo control for the determination of the acamprosate-specific effects. Moreover, no studies have yet assessed the genetic contribution to sobriety vs. other treatment outcomes. Therefore, Project 1 will search for genetic markers associated with acamprosate vs. placebo treatment response in AUD patients on a genome-wide scale in the combined sample including alcoholics treated by acamprosate and placebo in the COMBINE, PREDICT and P20 CITA studies and a new sample of 800 AUD patients treated in community- based programs in a double blind randomized placebo controlled study of acamprosate. This will allow us to perform a meta-analyses of genome-wide association with AUD treatment outcomes in the largest combined sample used for pharmacogenomic studies in the field of alcoholism research (total N>2400). We will also assess the heritability explained by common polymorphisms and the genetic architecture for different measures of alcoholism treatment response. Finally, we will conduct pharmacometabolomic- and pharmacoimaging-guided pharmacogenetic study by selecting candidate targets for additional analyses in pathways related to metabolic and imaging markers associated with acamprosate response in Projects 2 and 3. We also use functional analyses in the neuronal-derived iPS cell lines described in Project 2 for functional validation of our findings. RELEVANCE (See instructions): Completion of these studies will provide evidence leading to individualized treatment selection for AUD patients and guide development of treatment strategies based on the biomarkers of response.