PHARMACOGENOMICS OF ACAMPROSATE TREATMENT OUTCOME

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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.