In an international study, Mayo Clinic researchers and collaborators have identified genetic markers that may help in identifying individuals who could benefit from the alcoholism treatment drug acamprosate. The findings, published in the journal Translational Psychiatry, show that patients carrying these genetic variants have longer periods of abstinence during the first three months of acamprosate treatment.
Acamprosate is a commonly prescribed drug used to aid patients in recovery from alcoholism. Mayo researchers studied the association between variation in candidate genes and the length of sobriety in alcohol-dependent patients treated with acamprosate in community-based programs. They found that, when other environmental and physiological factors were considered, patients with the common allele of the genetic variant rs2058878 located in the GRIN2B gene, stayed sober more days than those with a variant allele of the same polymorphism. This finding was replicated in a sample of alcohol-dependent patients treated with acamprosate in a study conducted by collaborators from Germany.
“This association finding is a first step towards development of a pharmacogenetic test allowing physicians to choose appropriate treatment for specific subgroups of alcohol-dependent patients,” says Victor Karpyak, M.D., Ph.D., Mayo Clinic psychiatrist and lead author of the article. “We believe that individualized treatment selection will eliminate the need for trial-and-error approaches and improve treatment efficacy in patients with alcohol use disorders.”
The Mayo findings support evidence implicating an important role of the N-Methyl-D-aspartate (NMDA) receptors in the treatment effects of acamprosate. The researchers say more studies are needed to determine potential importance of identified genetic variants in the longer-term effects of acamprosate, as well as the molecular and physiological mechanisms behind the drug’s action.
About this Genetics research
The study was funded in part by the Mayo Clinic Center for Individualized Medicine; the SC Johnson Genomics of Addiction Program at Mayo Clinic; the National Institutes of Health; the National Center for Advancing Translational Sciences; the National Genome Research Network of the German Federal Ministry of Education and Research; the Bundesministerium für Bildung und Forschung; and the Alfred Krupp von Bolen und Halbach-Stiftung (Foundation).
Other authors include J. M. Biernacka, Ph.D., Jennifer Geske, G.D. Jenkins, J.M. Cunningham, Ph.D., A.A. Leontovich, Ph.D., O.A. Abulseoud, M.D., Daniel Hall-Flavin, M.D., L.L. Loukianova, M.D., Ph.D., T.D. Schneekloth, M.D., M.K. Skime, Richard Weinshilboum, M.D., Mark Frye, M.D., and D.S. Choi, Ph.D., of Mayo Clinic; J. Ruegg, Karolinska Institutet; O. Kononenko, Uppsala University; J. Frank, M.D., M. Rietschel, M.D., F. Kiefer, M.D., and K. F. Mann, M.D., Mannheim-Heidelburg University; and M.M. Nöthen, M.D., University of Bonn.
Contact: Bob Nellis – Mayo Clinic Source:Mayo Clinic press release Image Source: The image is credited to PublicDomainPictures and is in the public domain Original Research: Full open access research for “Genetic markers associated with abstinence length in alcohol-dependent subjects treated with acamprosate ” by V M Karpyak, J M Biernacka, J R Geske, G D Jenkins, J M Cunningham, J Rüegg, O Kononenko, A A Leontovich, O A Abulseoud, D K Hall-Flavin, L L Loukianova, T D Schneekloth, M K Skime, J Frank, M M Nöthen, M Rietschel, F Kiefer, K F Mann, R M Weinshilboum, M A Frye and D S Choi in Translational Psychiatry. Published online October 7 2014 doi:10.1038/tp.2014.103
Genetic markers associated with abstinence length in alcohol-dependent subjects treated with acamprosate
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.
“Genetic markers associated with abstinence length in alcohol-dependent subjects treated with acamprosate ” by V M Karpyak, J M Biernacka, J R Geske, G D Jenkins, J M Cunningham, J Rüegg, O Kononenko, A A Leontovich, O A Abulseoud, D K Hall-Flavin, L L Loukianova, T D Schneekloth, M K Skime, J Frank, M M Nöthen, M Rietschel, F Kiefer, K F Mann, R M Weinshilboum, M A Frye and D S Choi in Translational Psychiatry. doi:10.1038/tp.2014.103.