AbstractLarge meta-analyses indicate that acamprosate and naltrexone improve alcohol use disorder(AUD) treatment outcomes. However, these medications are only effective in a subset ofindividuals with AUDs, prompting the need for reliable predictors of treatment outcomes that canbe used to personalize treatment selection optimizing clinical benefits. It is widely known thatgenetic variation contributes to inter-individual differences in drug response, and it is expectedthat genomic factors can aid in prediction of clinical response to treatment of alcoholdependence. Prior candidate gene studies have identified several genetic variations associatedwith differential outcomes following treatment of alcohol dependence. However, no genome-wide pharmacogenomic studies of acamprosate or naltrexone treatment response have beenpublished. We propose to perform a comprehensive set of genome-wide association studiesusing samples from three of the largest studies of acamprosate and naltrexone completed todate (COMBINE, PREDICT and CITA), to identify genetic markers associated with AUDtreatment outcomes. Data from patients treated with acamprosate, naltrexone, or placebo willbe 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 singlenucleotide polymorphisms, as a powerful approach to aggregate modest genetic associationsignals to identify biological pathways involved in treatment outcomes and drug-specificresponse. The comprehensive genome-wide search for genetic markers associated withresponse to acamprosate and naltrexone may not only provide essential information foradvancement of precision medicine for AUDs, but may also advance knowledge about themechanism of action of these medications enabling further drug discovery. Being the first studyof its kind, this exploratory/developmental R21 grant will also provide critical information fordesigning future studies aimed at developing genomic predictors of AUD treatment response.
|Effective start/end date||7/15/16 → 6/30/18|
- National Institutes of Health: $268,313.00
Genome-Wide Association Study