Genetic variants associated with acamprosate treatment response in alcohol use disorder patients: A multiple omics study

Abstract

Background and Purpose Acamprosate is an anti‐craving drug used for the pharmacotherapy of alcohol use disorder (AUD). However, only some patients achieve optimal therapeutic outcomes. This study was designed to explore differences in metabolomic profiles between patients who maintained sobriety and those who relapsed, to determine whether those differences provide insight into variation in acamprosate treatment response phenotypes. Experimental Approach We previously conducted an acamprosate trial involving 442 AUD patients, and 267 of these subjects presented themselves for a 3‐month follow‐up. The primary outcome was abstinence. Clinical information, genomic data and metabolomics data were collected. Baseline plasma samples were assayed using targeted metabolomics. Key Results Baseline plasma arginine, threonine, α‐aminoadipic acid and ethanolamine concentrations were associated with acamprosate treatment outcomes and baseline craving intensity, a measure that has been associated with acamprosate treatment response. We next applied a pharmacometabolomics‐informed genome‐wide association study (GWAS) strategy to identify genetic variants that might contribute to variations in plasma metabolomic profiles that were associated with craving and/or acamprosate treatment outcome. Gene expression data for induced pluripotent stem cell‐derived forebrain astrocytes showed that a series of genes identified during the metabolomics‐informed GWAS were ethanol responsive. Furthermore, a large number of those genes could be regulated by acamprosate. Finally, we identified a series of single nucleotide polymorphisms that were associated with acamprosate treatment outcomes. Conclusion and Implications These results serve as an important step towards advancing our understanding of disease pathophysiology and drug action responsible for variation in acamprosate response and alcohol craving in AUD patients.

Genome-wide association study for circulating FGF21 in patients with alcohol use disorder: Molecular links between the SNHG16 locus and catecholamine metabolism

“…We set out to 1) measure plasma FGF21 levels using the Olink proteomic platform, 2) apply our established pharmaco-omics-informed genomics research strategy to identify genetic variants that might associate with levels of FGF21, and 3) functionally and mechanistically pursue “signals” coming from that GWAS. This research strategy has been used repeatedly to generate and test genomic and pharmacogenomic hypotheses and has proven to be a powerful research tool for identifying novel biology [ 9 , [24] , [25] , [26] ]. Specifically, we previously recruited 442 subjects with AUD for an acamprosate clinical trial ( Table 1 ) [ 27 ].…”

“…As a result, the inclusion of other omics data may offer a more comprehensive view of overall molecular variation that contributes to individual differences in response to drug therapy or disease susceptibility than would genomics alone. This research strategy has limitations, but it has already helped us understand the underlying biology of several neuropsychiatric diseases [ 9 , 10 , 24 ].…”

“…We designed the present study to apply our established pharmaco-omics-informed genomics research strategy to identify genetic variants that might contribute to the concentrations of plasma FGF21 and its functional role in AUD. This study is similar in design to previous pharmacogenomic studies that we have successfully performed identifying selective serotonin reuptake inhibitor treatment response in patients with major depressive disorder (9–11) [ 24 ] and acamprosate treatment response in patients with AUD [ 9 , 10 ].…”

Molecular mechanisms involved in alcohol craving, IRF3, and endoplasmic reticulum stress: a multi-omics study

“…The primary outcome of the clinical trial was acamprosate treatment response [ 21 , 22 ]. We previously identified alcohol craving as the most significant clinical phenotype associated with treatment outcomes [ 23 , 24 ]. Specifically, higher baseline craving intensity was associated with relapse to alcohol use during the three months of acamprosate treatment [ 22 , 23 , 25 ].…”

Plasma TNFSF10 levels associated with acamprosate treatment response in patients with alcohol use disorder

“…Acamprosate has been approved in the United States by the FDA for the treatment of alcohol use disorder (AUD). However, only a subset of patients achieves optimal treatment outcomes ( Ho et al, 2022a ). Acamprosate is not protein-bound; nor is it metabolized; and it is excreted unchanged in the urine ( Más-Serrano et al, 2000 ; Kalk and Lingford-Hughes, 2014 ).…”