PHARMACOGENOMICS OF ACAMPROSATE TREATMENT OUTCOME

阿坎酸治疗结果的药物基因组学

• 批准号: 10000815
• 负责人: Joanna M Biernacka
• 金额: $ 71.98万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10000815
• 关键词: Alcoholism; Anterior; Antidepressive Agents; Biological; Biological Markers; Brain imaging; Candidate Disease Gene; Categories; Cell Line; Clinical Data; Cohort Studies; Communities; Data; Development; Double-Blind Method; Drug Controls; Economics; Evidence based treatment; Gene Frequency; Genes; Genetic; Genetic Markers; Genetic Polymorphism; Genetic Variation; Glutamates; Goals; Health; Heavy Drinking; Heritability; Human; Instruction; Investigation; Left; Length; Link; Measures; Meta-Analysis; Metabolic Marker; Minor; Naltrexone; Neurons; Outcome; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacogenetics; Pharmacogenomics; Pharmacometabolomics; Phenotype; Placebo Control; Placebos; Plasma; Prefrontal Cortex; Randomized; Recommendation; Research; Sampling; Sampling Studies; Selection for Treatments; Selective Serotonin Reuptake Inhibitor; Serum; Signal Transduction; Source; Testing; Treatment outcome; Validation; Variant; acamprosate; alcohol consequences; alcohol craving; alcohol response; alcohol use disorder; alcoholism therapy; arm; base; behavioral phenotyping; brain tissue; cohort; cost; genetic architecture; genetic association; genome wide association study; genome-wide; genome-wide analysis; image guided; imaging biomarker; imaging study; improved; individualized medicine; induced pluripotent stem cell; innovation; metabolomics; neuroimaging; personalized medicine; predicting response; primary outcome; problem drinker; programs; randomized placebo controlled study; response; response biomarker; sobriety; therapy development; treatment response; treatment strategy

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.

酒精使用障碍(AUD)的经济和健康后果需要有效的治疗 战略。反应生物标记物的发现有望通过允许 治疗选择的个性化。我们的初步发现表明，戒酒与 氨基己酸酯治疗的酒精患者GRIN2B基因多态性和血浆谷氨酸的变化 级别。我们的神经成像数据表明，左侧前额叶背外侧的谷氨酸水平与 大脑皮层对酒精的渴求和前扣带回谷氨酸水平的降低 无氨基己酸酯治疗。然而，之前的研究使用了一组有限的候选基因，并且没有包括 安慰剂对照，用于确定氨基己酸酯的特定效应。此外，目前还没有研究表明 与其他治疗结果相比，评估了基因对戒酒的贡献。因此，项目1将搜索 寻找与服用阿卡米松与安慰剂治疗反应相关的遗传标记 联合样本中的全基因组范围包括接受阿卡米松和安慰剂治疗的酗酒者 结合、预测和P20 CITA研究和社区治疗的800名AUD患者的新样本- 氨基己酸酯的双盲、随机、安慰剂对照研究。这将使我们能够 对全基因组与AUD治疗结果之间的最大联合结果进行荟萃分析 用于酒精中毒研究领域药物基因组学研究的样本(共2400份)。我们还将 评估由常见多态和不同基因结构解释的遗传力 酒精中毒治疗反应的测量。最后，我们将进行药物代谢-和 通过选择候选靶点进行额外分析的药物显像学指导的药物遗传学研究 项目2和项目2中与氨基己酸酯反应相关的代谢和成像标记物的相关途径 3.我们还在项目2中描述的神经源性iPS细胞系中使用功能分析 验证我们的发现。 相关性(请参阅说明)： 这些研究的完成将为AUD的个体化治疗选择提供证据 并根据反应的生物标志物指导患者制定治疗策略。