Variation in GABRA2 predicts drinking behavior in project MATCH subjects.
ABSTRACT: Previous studies demonstrated, and replicated, an association between single nucleotide polymorphisms (SNPs) within the GABRA2 gene and risk for alcohol dependence. The present study examines the association of a GABRA2 SNP with another definition of alcohol involvement and with the effects of psychosocial treatment.European-American subjects (n = 812, 73.4% male) provided DNA samples for the analysis. All were participants in Project Matching Alcoholism Treatment to Client Heterogeneity (MATCH), a multi-center randomized clinical trial evaluating the efficacy of 3 types of psychosocial treatment for alcoholism: Cognitive Behavioral Therapy (CBT), Motivational Enhancement Therapy (MET), or twelve-step facilitation (TSF). The daily probabilities of drinking and heavy drinking were estimated during the 12-week treatment and 12-month post-treatment periods.Subjects homozygous for the allele associated with low risk for alcohol dependence in previous studies had lower daily probabilities of drinking and heavy drinking in the present study. This low-risk allele was also associated with a greater difference in drinking outcomes between the treatments. In addition, it enhanced the relative superiority of TSF over CBT and MET. Population stratification was excluded as a confound using ancestry informative marker analysis.The assessment of genetic vulnerability may be relevant to studies of the efficacy of psychosocial treatment: GABRA2 genotype modifies the variance in drinking and can therefore moderate power for resolving differences between treatments.
Project description:BACKGROUND:Subjective perceptions of alcohol intoxication are associated with altered risk for alcohol abuse and dependence. Acute adaptation of these perceptions may influence such risk and may involve genes associated with pleasant perceptions or the relief of anxiety. This study assessed the effect of variation in the GABAA receptor genes GABRG1 and GABRA2 and recent drinking history on the acute adaptation of subjective responses to alcohol. METHODS:One hundred and thirty-two nondependent moderate to heavy drinkers, aged 21 to 27, participated in 2 single-blind, counterbalanced sessions, approximately 1 week apart. One session was an intravenous alcohol "clamp," during which breath alcohol concentration was held steady at 60 mg/dl (60 mg%) for 3 hours, and the other an identical session using saline infusion. Subjective perceptions of Intoxication, Enjoyment, Stimulation, Relaxation, Anxiety, Tiredness, and Estimated Number of Drinks were acquired before (baseline), and during the first and final 45 minutes of the clamp. A placebo-adjusted index of the subject's acute adaptation to alcohol was calculated for each of the 7 subjective measures and used in a principal component analysis to create a single aggregate estimate for each subject's adaptive response to alcohol. Analysis of covariance tested whether GABRA2 and GABRG1 single nucleotide polymorphism (SNP) genotypes, gender, placebo session, family history of alcoholism, recent drinking history, and the genotype × recent drinking history interaction significantly predicted the adaptive response. RESULTS:Recent drinking history (p = 0.01), and recent drinking history × genotype interaction (p = 0.01) were significantly associated with acute adaptation of the subjective responses to alcohol for the GABRA2 SNP rs279858. CONCLUSIONS:Higher recent drinking was found to be associated with reduced acute tolerance to positive, stimulating effects of alcohol in carriers of the rs279858 risk allele. We postulate that the GABRA2 effect on alcohol dependence may, in part, be due to its effect on subjective responses to alcohol.
Project description:In this article, we review studies of genetic moderators of the response to medications to treat alcohol dependence, the acute response to alcohol, and the response to the psychotherapeutic treatment of heavy drinking. We consider four neurotransmitter systems: opioidergic, dopaminergic, GABAergic, and glutamatergic and focus on one receptor protein in each: OPRM1 (the &#micro;-opioid receptor gene), DRD4 (the D(4) dopamine receptor gene), GABRA2 (GABA(A) receptor alpha-2 subunit gene), and GRIK1 (the kainite receptor GluR5 subunit gene). We conclude that because parallel developments in alcoholism treatment and the genetics of alcohol dependence are beginning to converge, using genotypic information, it may be possible to match patients with specific treatments. Of greatest clinical relevance is the finding that the presence of an Asp40 allele in OPRM1 modestly predicts a better response to naltrexone treatment. Promising findings include the observations that a polymorphism in GABRA2 predicts the response to specific psychotherapies; a polymorphism in DRD4 predicts the effects of the antipsychotic olanzapine on craving for alcohol and drinking behavior; and a polymorphism in GRIKI predicts adverse events resulting from treatment with the anticonvulsant topiramate. Although variants in other genes have been associated with the risk for alcohol dependence, they have not been studied as moderators of the response either to treatment or acute alcohol administration. We recommend that, whenever possible, treatment trials include the collection of DNA samples to permit pharmacogenetic analyses, and that such analyses look broadly for relevant genetic variation.
Project description:Excessive alcohol consumption is one of the leading causes of preventable death in the United States. Approximately 14% of those who use alcohol meet criteria during their lifetime for alcohol dependence, which is characterized by tolerance, withdrawal, inability to stop drinking, and continued drinking despite serious psychological or physiological problems. We explored genetic influences on alcohol dependence among 1,897 European-American and African-American subjects with alcohol dependence compared with 1,932 unrelated, alcohol-exposed, nondependent controls. Constitutional DNA of each subject was genotyped using the Illumina 1M beadchip. Fifteen SNPs yielded P < 10(-5), but in two independent replication series, no SNP passed a replication threshold of P < 0.05. Candidate gene GABRA2, which encodes the GABA receptor alpha2 subunit, was evaluated independently. Five SNPs at GABRA2 yielded nominal (uncorrected) P < 0.05, with odds ratios between 1.11 and 1.16. Further dissection of the alcoholism phenotype, to disentangle the influence of comorbid substance-use disorders, will be a next step in identifying genetic variants associated with alcohol dependence.
Project description:Alcohol is widely consumed; however, excessive use creates serious physical, psychological and social problems and contributes to the pathogenesis of many diseases. Alcohol use disorders (that is, alcohol dependence and alcohol abuse) are maladaptive patterns of excessive drinking that lead to serious problems. Abundant evidence indicates that alcohol dependence (alcoholism) is a complex genetic disease, with variations in a large number of genes affecting a person's risk of alcoholism. Some of these genes have been identified, including two genes involved in the metabolism of alcohol (ADH1B and ALDH2) that have the strongest known affects on the risk of alcoholism. Studies continue to reveal other genes in which variants affect the risk of alcoholism or related traits, including GABRA2, CHRM2, KCNJ6 and AUTS2. As more variants are analysed and studies are combined for meta-analysis to achieve increased sample sizes, an improved picture of the many genes and pathways that affect the risk of alcoholism will be possible.
Project description:To estimate differences in post-treatment psychosocial functioning among treatment 'failures' (i.e. heavy drinkers, defined as 4+/5+ drinks for women/men) from two large multi-site clinical trials and to compare these levels of functioning to those of the purported treatment 'successes' (i.e. non-heavy drinkers).Separate latent profile analyses of data from two of the largest alcohol clinical trials conducted in the United States, COMBINE (Combined Pharmacotherapies and Behavioral Interventions) and Project MATCH (Matching Alcoholism Treatments to Client Heterogeneity), comparing psychosocial outcomes across derived classes of heterogeneous treatment responders.Eleven US academic sites in COMBINE, 27 US treatment sites local to nine research sites in Project MATCH.A total of 962 individuals in COMBINE (69% male, 77% white, mean age: 44 years) treated January 2001 to January 2004 and 1528 individuals in Project MATCH (75% male, 80% white, mean age: 40 years) treated April 1991 to September 1994.In COMBINE, we analyzed health, quality of life, mental health symptoms and alcohol consequences 12 months post-baseline. In Project MATCH, we examined social functioning, mental health symptoms and alcohol consequences 15 months post-baseline.Latent profile analysis of measures of functioning in both samples supported a three-profile solution for the group of treatment 'failures', characterized by high-, average- and low-functioning individuals. The high-functioning treatment 'failures' generally performed better across measures of psychosocial functioning at follow-up than participants designated treatment 'successes' by virtue of being abstainers or light drinkers.Current United States Food and Drug Administration guidance to use heavy drinking as indicative of treatment 'failure' fails to take into account substantial psychosocial improvements made by individuals who continue occasionally to drink heavily post-treatment.
Project description:Survival analysis was used to explore the addition of a single nucleotide polymorphism (SNP) and covariates (sex, interview age, and ancestry) on a previously published model's ability to predict onset of drinking. A SNP variant of rs279871, in the chromosome 4 gene encoding gamma-aminobutyric acid receptor (GABRA2), was selected due to its associations with alcoholism in young adults and with behaviors that increased risk for early drinking.A subsample of 674 adolescents (ages 14-17) participating in the Collaborative Study on the Genetics of Alcoholism (COGA) was examined using a previously derived Cox proportional hazards model containing: 1) number of non-drinking related conduct disorder (CD) symptoms, 2) membership in a high-risk alcohol-dependent (AD) family, 3) most best friends drank (MBFD), 4) Achenbach Youth Self Report (YSR) externalizing score, and 5) YSR social problems score. The above covariates along with the SNP variant of GABRA2, rs279871, were added to this model. Five new prototype models were examined. The most parsimonious model was chosen based on likelihood ratio tests and model fit statistics.The final model contained four of the five original predictors (YSR social problems score was no longer significant and hence dropped from subsequent models), the three covariates, and a recessive GABRA2 rs279871 TT genotype (two copies of the high-risk allele containing thymine). The model indicated that adolescents with the high-risk TT genotype were more likely to begin drinking than those without this genotype.The joint effect of the gene (rs279871 TT genotype) and environment (MBFD) on adolescent alcohol initiation is additive, but not interactive, after controlling for behavior problems (CD and YSR externalizing score). This suggests that the impact of the high-risk TT genotype on the onset of drinking is affected by controlling for peer drinking and does not include genotype-by-environment interactions.
Project description:Various statistical methods have been used for data analysis in alcohol treatment studies. Trajectory analyses can better capture differences in treatment effects and may provide insight on the optimal duration of future clinical trials and grace periods. This improves on the limitation of commonly used parametric (e.g., linear) methods that cannot capture nonlinear temporal trends in the data.We propose an exploratory approach, using more flexible smoothing mixed effects models, more accurately to characterize the temporal patterns of the drinking data. We estimated the trajectories of the treatment arms for data sets from 2 sources: a multisite topiramate study, and the Combined Pharmacotherapies (acamprosate and naltrexone) and Behavioral Interventions study.Our methods illustrate that drinking outcomes of both the topiramate and placebo arms declined over the entire course of the trial but with a greater rate of decline for the topiramate arm. By the point-wise confidence intervals, the heavy drinking probabilities for the topiramate arm might differ from those of the placebo arm as early as week 2. Furthermore, the heavy drinking probabilities of both arms seemed to stabilize at the end of the study. Overall, naltrexone was better than placebo in reducing drinking over time yet was not different from placebo for subjects receiving the combination of a brief medical management and an intensive combined behavioral intervention.The estimated trajectory plots clearly showed nonlinear temporal trends of the treatment with different medications on drinking outcomes and offered more detailed interpretation of the results. This trajectory analysis approach is proposed as a valid exploratory method for evaluating efficacy in pharmacotherapy trials in alcoholism.
Project description:Naltrexone (NTX) has proven to be effective with alcoholics in treatment, with most controlled clinical trials showing beneficial effects on heavy drinking rates. However, little is known about the behavioral mechanisms underlying the effects of NTX on drinking, or about patient characteristics that may moderate NTX's effects on drinking. In this study, ecological momentary assessment (EMA) techniques were used to investigate some of the putative mechanisms of naltrexone's effects on drinking in heavy drinkers who were not seeking treatment for alcohol problems. Polymorphisms in the D4 dopamine receptor (DRD4) gene and the mu-opiate receptor (OPRM1) gene, family history of alcohol problems, age of onset of alcoholism and gender were explored as potential moderators of NTX's effects.After a 1-week placebo lead-in period, heavy drinkers (n = 180), 63% of whom were alcohol-dependent, were randomized to 3 weeks of daily naltrexone (50 mg) or placebo. Throughout the study, participants used EMA on palm-pilot computers to enter, in real time, drink data, urge levels, and subjective effects of alcohol consumption.Naltrexone reduced percentage drinking days in all participants and reduced percent heavy drinking days in DRD4-L individuals; NTX decreased urge levels in participants with younger age of alcoholism onset; NTX increased time between drinks in participants who had more relatives with alcohol problems; and NTX reduced the stimulating effects of alcohol in women. OPRM1 status did not moderate any of NTX's effects.These results confirm earlier findings of NTX's effects on drinking and related subjective effects, and extend them by describing individual difference variables that moderate these effects in the natural environment, using data collected in real time.
Project description:The goal of this cross-sectional study was to assess the relationship of alcohol craving with biopsychosocial and addiction factors that are clinically pertinent to alcoholism treatment. Alcohol craving was assessed in 315 treatment-seeking, alcohol dependent subjects using the Penn Alcohol Craving Scale questionnaire. Standard validated questionnaires were used to evaluate a variety of biological, addiction, psychological, psychiatric, and social factors. Individual covariates of craving included age, race, problematic consequences of drinking, heavy drinking, motivation for change, mood disturbance, sleep problems, and social supports. In a multivariate analysis (R(2)= .34), alcohol craving was positively associated with mood disturbance, heavy drinking, readiness for change, and negatively associated with age. The results from this study suggest that alcohol craving is a complex phenomenon influenced by multiple factors.
Project description:BACKGROUND AND AIMS:There is evidence that low-risk drinking is possible during the course of alcohol treatment and can be maintained following treatment. Our aim was to identify characteristics associated with low-risk drinking during treatment in a large sample of individuals as they received treatment for alcohol dependence. DESIGN:Integrated analysis of data from the Combined Pharmacotherapies and Behavioral Intervention (COMBINE) study, Project MATCH (Matching Alcoholism Treatments to Client Heterogeneity) and the United Kingdom Alcohol Treatment Trial (UKATT) using repeated-measures latent class analysis to identify patterns of drinking and predictors of low-risk drinking patterns during treatment. SETTING:United States and United Kingdom. PARTICIPANTS:Patients (n = 3589) with alcohol dependence receiving treatment in an alcohol clinical trial were primarily male (73.0%), white (82.0%) and non-married (41.7%), with an average age of 42.0 (standard deviation = 10.7). MEASUREMENTS:Self-reported weekly alcohol consumption during treatment was assessed using the Form-90 and validated with biological verification or collateral informants. FINDINGS:Seven patterns of drinking during treatment were identified: persistent heavy drinking (18.7% of the sample), increasing heavy drinking (9.6%), heavy and low-risk drinking (6.7%), heavy drinking alternating with abstinence (7.9%), low-risk drinking (6.8%), increasing low-risk drinking (10.5%) and abstinence (39.8%). Lower alcohol dependence severity and fewer drinks per day at baseline significantly predicted low-risk drinking patterns [e.g. each additional drink prior to baseline predicted a 27% increase in the odds of expected classification in heavy drinking versus low-risk drinking patterns; odds ratio = 1.27 (95% confidence interval (CI) = 1.10, 1.47, P = 0.002]. Greater negative mood and more heavy drinkers in the social network were significant predictors of expected membership in heavier drinking patterns. CONCLUSIONS:Low-risk drinking is achievable for some individuals as they undergo treatment for alcohol dependence. Individuals with lower dependence severity, less baseline drinking, fewer negative mood symptoms and fewer heavy drinkers in their social networks have a higher probability of achieving low-risk drinking during treatment.