Pharmacogenomics of Treatment Outcomes in Alcohol Use Disorders

摘要 大型荟萃分析表明，阿坎酸和纳洛酮改善酒精使用障碍 (AUD)治疗结果。然而，这些药物仅在以下子集中有效： AUDs患者，提示需要可靠的治疗结果预测因子， 用于个性化治疗选择，优化临床获益。众所周知， 遗传变异有助于药物反应的个体间差异，预计 基因组因素可以帮助预测酒精治疗的临床反应， 依赖先前的候选基因研究已经确定了几个相关的遗传变异 酒精依赖治疗后的不同结果。但是，没有基因组- 对阿坎酸或纳洛酮治疗反应的广泛药物基因组学研究已经 公开.我们建议进行一套全面的全基因组关联研究 使用来自三项最大的阿坎酸和纳洛酮研究的样本， 日期（联合收割机、PREDICT和CITA），以识别与AUD相关的遗传标记 治疗结果。接受阿坎酸、纳洛酮或安慰剂治疗的患者的数据将 用于识别饮酒结果的预测因素，而不考虑药物干预， 而分层分析和基因-药物相互作用分析将用于确定治疗- 阿坎酸和纳洛酮治疗结果的特异性（即药物基因组学）预测因子。 基于途径的基因集分析将补充单个基因的全基因组关联分析 核苷酸多态性，作为一种强有力的方法，聚合适度的遗传关联， 识别参与治疗结果和药物特异性的生物学途径的信号 反应对与以下疾病相关的遗传标记的全基因组搜索 对阿坎酸和纳洛酮的反应不仅可以提供 提高AUD的精准医学，但也可能提高对 这些药物的作用机制，使进一步的药物发现。作为第一个研究 这种探索性/发展性R21赠款还将为以下方面提供关键信息： 设计未来的研究，旨在开发AUD治疗反应的基因组预测因子。

Abstract Large meta-analyses indicate that acamprosate and naltrexone improve alcohol use disorder (AUD) treatment outcomes. However, these medications are only effective in a subset of individuals with AUDs, prompting the need for reliable predictors of treatment outcomes that can be used to personalize treatment selection optimizing clinical benefits. It is widely known that genetic variation contributes to inter-individual differences in drug response, and it is expected that genomic factors can aid in prediction of clinical response to treatment of alcohol dependence. Prior candidate gene studies have identified several genetic variations associated with differential outcomes following treatment of alcohol dependence. However, no genome- wide pharmacogenomic studies of acamprosate or naltrexone treatment response have been published. We propose to perform a comprehensive set of genome-wide association studies using samples from three of the largest studies of acamprosate and naltrexone completed to date (COMBINE, PREDICT and CITA), to identify genetic markers associated with AUD treatment outcomes. Data from patients treated with acamprosate, naltrexone, or placebo will be used to identify predictors of drinking outcomes regardless of pharmacological intervention, while stratified analyses and gene-drug interaction analyses will be used to identify treatment- specific (i.e. pharmacogenomic) predictors of acamprosate and naltrexone treatment outcomes. Pathway-based gene set analyses will complement genome-wide association analyses of single nucleotide polymorphisms, as a powerful approach to aggregate modest genetic association signals to identify biological pathways involved in treatment outcomes and drug-specific response. The comprehensive genome-wide search for genetic markers associated with response to acamprosate and naltrexone may not only provide essential information for advancement of precision medicine for AUDs, but may also advance knowledge about the mechanism of action of these medications enabling further drug discovery. Being the first study of its kind, this exploratory/developmental R21 grant will also provide critical information for designing future studies aimed at developing genomic predictors of AUD treatment response.