Biomarker for craving and acamprosate treatment response in patients with alcohol use disorder: insights from multi-omics.

To date, no objective biochemical markers have been linked to alcohol craving intensity or response to drug treatment for alcohol use disorder (AUD). To address this gap, we aimed to identify potential biomarkers associated with alcohol craving intensity using multi-omics data from the Mayo Clinic acamprosate study-the largest acamprosate trial of its kind and the only one with multi-omics data. In this open-label trial, all 442 participants received acamprosate treatment for three months, during which we collected extensive clinical data, including alcohol consumption and craving intensity. Baseline plasma samples were analyzed using the OLINK "Explore Inflammation" panel, and we employed patient-derived induced pluripotent stem cells (iPSCs) as a functional genomic model. Our findings revealed that baseline craving intensity was the most significant clinical predictor of relapse (p: 9.36E-06). Baseline plasma levels of HSD11B1, an enzyme that converts inactive cortisone to active cortisol, were associated with both craving intensity and acamprosate treatment outcomes. Additionally, baseline plasma cortisol levels showed a positive correlation with craving intensity. Notably, a genome-wide association study (GWAS) for plasma cortisol levels identified significant signals within the KHNYN and CBLN3 gene cluster on chromosome 14. Even more striking, this SNP was also associated with acamprosate treatment outcomes. Functional genomic studies using patient-derived iPSC further suggest that KHNYN and CBLN3 could regulate cortisol metabolism and interferon signaling. In summary, this study leverages multi-omics data from one of the most extensive acamprosate trials to date to identify potential biomarkers for alcohol craving intensity and treatment response.