Plasma TNFSF10B levels associated with acamprosate treatment response in patients with alcohol use disorder

Acamprosate is an anti-craving drug used in alcohol use disorder (AUD) pharmacotherapy. However, only a subset of patients achieves optimal treatment outcomes. The identification of predictive biomarkers of acamprosate treatment response in patients with AUD would be a substantial advance in addiction medicine. We designed this study to use proteomics data as a quantitative biological trait as a step toward identifying inflammatory modulators that might be associated with acamprosate treatment outcomes. The NIAAA-funded Mayo Clinic Center for the Individualized Treatment of Alcoholism study had previously recruited 442 AUD patients who received three months of acamprosate treatment. However, only 267 subjects returned for the 3-month follow-up visit and, as a result, had treatment outcome information available. Baseline alcohol craving intensity was the most significant predictor of acamprosate treatment outcomes. Baseline plasma TNFSF10 concentration was associated with alcohol craving intensity and variation in acamprosate treatment outcomes among AUD patients. We also performed RNA sequencing using baseline peripheral blood mononuclear cells from AUD patients with known acamprosate treatment outcomes which revealed that inflammation-related pathways were highly associated with relapse to alcohol use during the three months of acamprosate treatment. These observations represent an important step toward advancing our understanding of the pathophysiology of AUD and molecular mechanisms associated with acamprosate treatment response. In conclusion, applying omics-based approaches may be a practical approach for identifying biologic markers that could potentially predict alcohol craving intensity and acamprosate treatment response. Peripheral blood mononuclear cells (PBMCs) samples were isolated from 15 ml of whole blood before acamprosate treatment using Ficoll density gradient centrifugation. We lysed the cells in Trizol and extracted total RNA using the RNeasy mini kit (Qiagen, Valencia, CA, USA). The RNA integrity numbers (RIN) were between 8.5-9.2 for the PBMC samples (relapse: n=27, non-relapse: n=26). RNA-seq experiments were conducted by GENEWIZ using an Illumina HiSeq 4000 with eight samples in each lane using 100bp paired end index reads. Fastq files containing paired RNA-Seq reads were aligned with STAR (23) against the UCSC human reference genome (hg19). We performed RNA-seq differential expression analysis using the DESeq2 package with default parameters.