Pharmacogenomics of Acamprosate Treatment Outcome (Supplement)

ABSTRACT 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, we are searching 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 600 AUD patients treated in community- based programs in a double-blind randomized placebo-controlled study of acamprosate. This allows us to perform a meta-analysis 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 are also assessing the heritability explained by common polymorphisms and the genetic architecture for different measures of alcoholism treatment response. We are using functional analyses in the neuronal-derived iPS cell lines for functional validation of our findings. Due to COVID related hardships, our recruitment is currently behind schedule. Specifically, we were required to continue the employment of the research staff when recruitment was not possible or reduced due to COVID related restrictions (full closure of the recruitment sites for up to 3 months and reopening at 50% capacity to comply with social distance requirements for subsequent 15 months). This resulted in recruiting approximately 70 to 80 subjects less compared to plan for that period. To compensate for this loss, we request $95,000 to support 2 coordinators for ~ 6.5 calendar months, which may allow us to recruit up to 70 - 80 additional study subjects in the remaining study time. The lack of support for this effort may result in decreased statistical power necessary to achieve study goals – i.e. identify biomarkers associated with acamprosate treatment response.