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Karpyak VM1, Biernacka JM1, Geske J1, Jenkins G1, Cunningham JM1, Rüegg J2, Kononenko O3, Leontovich AA1, Abulseoud O1, Hall-Flavin1 D, Loukianova LL1, Schneekloth, TD1, Skime M1, Frank J4, Nöthen MM5, Rietschel M4, Kiefer F4, Mann K4, Weinshilboum R1, Frye MA1, Choi DS1

1Mayo Clinic, Rochester, MN, USA
2Department of Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden
3Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden
4Central Institute of Mental Health, Mannheim, Germany
5University of Bonn, Bonn, Germany

Acamprosate extends sobriety length in some alcoholics and is believed to modify glycine and glutamate neurotransmission. However, it is not uniformly efficient and response predictors are not known. To identify such response predictors, we investigated associations of sobriety length with clinical characteristics of acamprosate-teated alcoholics and polymorphisms in candidate genes included in the glycine and glutamate neurotransmission pathways and genes previously implicated response.
We conducted association analyses in the discovery sample of 225 alcoholics treated with acamprosate for three months in the community based treatment programs in the upper Midwest of the United States. Replication analyses for the top association findings were conducted using data from 110 male alcoholics treated with acamprosate in the study PREDICT. Statistical models were adjusted for relevant covariates, including recruitment site and baseline clinical variables associated with response.
In the discovery sample, shorter abstinence was associated with increased craving and shorter abstinence before initiation of acamprosate treatment. After adjustment for covariates, length of sobriety during acamprosate treatment was associated with the GRIN2B rs2058878 (p=4.6×10-5). In the replication sample, shorter abstinence was associated with increased craving, increased depressive mood score, and higher alcohol consumption before treatment. Association of sobriety length with GRIN2B rs2058878 was marginally significant (p=0.0675); as in the discovery sample, the minor A allele was associated with longer abstinence. Furthermore, rs2300272, which is in strong linkage disequilibrium with rs2058878, was also associated with abstinence length (p=0.049).
Our findings suggest that GRIN2B rs2058878 and rs2300272 SNPs may be pharmacogenetic markers predictive of the length of sobriety in acamprosate-treated alcoholics. Future studies should investigate usefulness of these biomarkers for individualized treatment selection and investigate the underlying mechanisms of this association.