title: Genetic markers associated with abstinence length in alcohol-dependent subjects treated with acamprosate.
abstract: Acamprosate supports abstinence in some alcohol-dependent subjects, yet predictors of response are unknown. To identify response biomarkers, we investigated associations of abstinence length with polymorphisms in candidate genes in glycine and glutamate neurotransmission pathways and genes previously implicated in acamprosate response. Association analyses were conducted in the discovery sample of 225 alcohol-dependent subjects treated with acamprosate for 3 months in community-based treatment programs in the United States. Data from 110 alcohol-dependent males treated with acamprosate in the study PREDICT were used for replication of the top association findings. 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 intensity of alcohol craving and lower number of days between the last drink and initiation of acamprosate treatment. After adjustment for covariates, length of abstinence 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. Association of abstinence 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). This is the first report of a replicated association of genetic markers with the length of abstinence in acamprosate-treated alcoholics. Investigation of the underlying mechanisms of this association and its usefulness for individualized treatment selection should follow.
authors.affiliation: Department of Psychiatry and Psychology, Mayo Clinic, Rochester, MN, USA.
authors.forename: V M
authors.initials: VM
authors.lastname: Karpyak
authors.affiliation: 1] Department of Psychiatry and Psychology, Mayo Clinic, Rochester, MN, USA [2] Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.
authors.forename: J M
authors.initials: JM
authors.lastname: Biernacka
authors.affiliation: Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.
authors.forename: J R
authors.initials: JR
authors.lastname: Geske
authors.affiliation: Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.
authors.forename: G D
authors.initials: GD
authors.lastname: Jenkins
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
authors.forename: J M
authors.initials: JM
authors.lastname: Cunningham
authors.affiliation: Department of Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden.
authors.forename: J
authors.initials: J
authors.lastname: Rüegg
authors.affiliation: Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden.
authors.forename: O
authors.initials: O
authors.lastname: Kononenko
authors.affiliation: Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.
authors.forename: A A
authors.initials: AA
authors.lastname: Leontovich
authors.affiliation: Department of Psychiatry and Psychology, Mayo Clinic, Rochester, MN, USA.
authors.forename: O A
authors.initials: OA
authors.lastname: Abulseoud
authors.affiliation: Department of Psychiatry and Psychology, Mayo Clinic, Rochester, MN, USA.
authors.forename: D K
authors.initials: DK
authors.lastname: Hall-Flavin
authors.affiliation: Department of Psychiatry and Psychology, Mayo Clinic, Rochester, MN, USA.
authors.forename: L L
authors.initials: LL
authors.lastname: Loukianova
authors.affiliation: Department of Psychiatry and Psychology, Mayo Clinic, Rochester, MN, USA.
authors.forename: T D
authors.initials: TD
authors.lastname: Schneekloth
authors.affiliation: Department of Psychiatry and Psychology, Mayo Clinic, Rochester, MN, USA.
authors.forename: M K
authors.initials: MK
authors.lastname: Skime
authors.affiliation: Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim/Heidelberg University, Mannheim, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Frank
authors.affiliation: Department of Genomics Life and Brain Research Centre, Institute of Human Genetics, University of Bonn, Bonn, Germany.
authors.forename: M M
authors.initials: MM
authors.lastname: Nöthen
authors.affiliation: Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim/Heidelberg University, Mannheim, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Rietschel
authors.affiliation: Department of Addictive Behavior and Addiction Medicine, Central Institute of Mental Health, Medical Faculty Mannheim/Heidelberg University, Mannheim, Germany.
authors.forename: F
authors.initials: F
authors.lastname: Kiefer
authors.affiliation: Department of Addictive Behavior and Addiction Medicine, Central Institute of Mental Health, Medical Faculty Mannheim/Heidelberg University, Mannheim, Germany.
authors.forename: K F
authors.initials: KF
authors.lastname: Mann
authors.affiliation: Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA.
authors.forename: R M
authors.initials: RM
authors.lastname: Weinshilboum
authors.affiliation: Department of Psychiatry and Psychology, Mayo Clinic, Rochester, MN, USA.
authors.forename: M A
authors.initials: MA
authors.lastname: Frye
authors.affiliation: 1] Department of Psychiatry and Psychology, Mayo Clinic, Rochester, MN, USA [2] Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA.
authors.forename: D S
authors.initials: DS
authors.lastname: Choi
mesh_terms: D000077443:Acamprosate; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000427:Alcohol Deterrents / Q000627:therapeutic use*; D000437:Alcoholism / Q000188:drug therapy* / Q000235:genetics*; D005260:Female; D005819:Genetic Markers / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D012074:Remission Induction; D013654:Taurine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D013997:Time Factors; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000427:Alcohol Deterrents; D005819:Genetic Markers; D013654:Taurine; D000077443:Acamprosate