Henry R. Kranzler

A Functional Polymorphism of the μ -Opioid Receptor Gene is Associated with Naltrexone Response in Alcohol-Dependent Patients

This study examined the association between two specific polymorphisms of the gene encoding the μ-opioid receptor and treatment outcomes in alcohol-dependent patients who were prescribed naltrexone or placebo. A total of 82 patients (71 of European descent) who were randomized to naltrexone and 59 who were randomized to placebo (all of European descent) in one of three randomized, placebo-controlled clinical trials of naltrexone were genotyped at the A+118G (Asn40Asp) and C+17T (Ala6Val) SNPs in the gene encoding the μ-opioid receptor (OPRM1). The association between genotype and drinking outcomes was measured over 12 weeks of treatment. In subjects of European descent, individuals with one or two copies of the Asp40 allele treated with naltrexone had significantly lower rates of relapse (p=0.044) and a longer time to return to heavy drinking (p=0.040) than those homozygous for the Asn40 allele. There were no differences in overall abstinence rates (p=0.611), nor were there differences in relapse rates or abstinence rates between the two genotype groups among those assigned to placebo. These preliminary results are consistent with prior literature demonstrating that the opioid system is involved in the reinforcing properties of alcohol and that allelic variation at OPRM1 is associated with differential response to a μ-receptor antagonist. If replicated, these results would help to identify alcohol-dependent individuals who may be most likely to respond to treatment with naltrexone.

Serotonin transporter protein (SLC6A4) allele and haplotype frequencies and linkage disequilibria in African- and European-American and Japanese populations and in alcohol-dependent subjects.

Abstract The SLC6A4 locus encodes the serotonin transporter, which in turn mediates the synaptic inactivation of the neurotransmitter serotonin. Two PCR-formatted polymorphisms at this locus have been described, the first of which is a variable number tandem repeat located in exon 2, and the second a repeat sequence polymorphism located in the promoter region. The latter polymorphism alters transcriptional activity of SLC6A4, and has been reported to be associated with anxiety and depression-related traits. We studied allele frequencies, and computed haplotype frequencies and linkage disequilibrium measures, for these two polymorphisms in European-American, African-American, and Japanese populations, and in a set of alcohol-dependent European-American subjects. Allele frequencies for both systems showed variation, with significant differences overall for each system, and significant differences between each pair of populations for both systems. Linkage disequilibrium also varied among the populations. There were no significant differences in allele or haplotype frequencies between the European-American population samples and alcohol-dependent subjects. The population differences demonstrate a potential for population stratification in association studies of either of these SLC6A4 polymorphisms. If genetic variation at this locus really is associated with behavioral variation, these results could reflect either different behavioral adaptations in different populations, or random genetic drift of a behaviorally important but selectively neutral polymorphism.

Give them prizes, and they will come: contingency management for treatment of alcohol dependence.

This study evaluated the efficacy of a contingency management (CM) procedure that provided opportunities to win prizes as reinforcers. At intake to outpatient treatment, 42 alcohol-dependent veterans were randomly assigned to receive standard treatment or standard treatment plus CM, in which they earned the chance to win prizes for submitting negative Breathalyzer samples and completing steps toward treatment goals. Eighty-four percent of the CM participants were retained in treatment for an 8-week period compared with 22% of the standard treatment participants (p < .001). By the end of the treatment period, 69% of those receiving CM were still abstinent, but 61% of those receiving standard treatment had used alcohol (p < .05). These results support the efficacy of this CM procedure. Participants earned an average of

Meta‐analysis of the association of a functional serotonin transporter promoter polymorphism with alcohol dependence

200 in prizes. This CM procedure may be suitable for use in standard treatment settings because prizes can be solicited from the community.

Allelic and haplotypic association of GABRA2 with alcohol dependence.

The neurotransmitter serotonin (5‐HT) has been shown to regulate alcohol consumption in both animals and humans. Since activity of the 5‐HT transporter protein (5‐HTT) regulates 5‐HT levels, the gene encoding this protein may contribute to the risk of alcohol dependence (AD). Studies of the association to AD of a functional insertion‐deletion polymorphism in the 5‐HTT‐linked promoter region (5‐HTTLPR) have yielded inconsistent results. We conducted a meta‐analysis of data from 17 published studies (including 3,489 alcoholics and 2,325 controls) investigating the association between 5‐HTTLPR alleles and AD. The frequency of the short (S) allele at 5‐HTTLPR was significantly associated with AD [odds ratio (OR) = 1.18, 95% CI = 1.03–1.33). Moreover, a greater association with the S allele was seen among individuals with AD complicated by either a co‐morbid psychiatric condition or an early‐onset or more severe AD subtype [OR = 1.34 (95% CI = 1.11–1.63)]. Allelic variation at 5‐HTTLPR contributes to risk for AD, with the greatest effect observed among individuals with a co‐occurring clinical feature.

Interaction of FKBP5 with childhood adversity on risk for post-traumatic stress disorder.

Alcohol dependence is a highly prevalent disorder that is associated with serious morbidity and mortality. Because the GABAA neurotransmitter receptor is an important mediator for several behavioral effects of alcohol, genes encoding GABA‐related proteins are functional candidates to influence risk of alcohol dependence. Two genome‐wide scans showed linkage of alcohol dependence to a region on chromosome 4p, which contains a cluster of genes encoding GABAA receptor subunits. A recent effort to fine map that region showed a haplotypic association of alcohol dependence to the gene encoding the GABAA receptor α‐2 subunit (GABRA2). We examined 10 single nucleotide polymorphisms (SNPs) spanning the coding region of this gene in samples of European American subjects with alcohol dependence (n = 446), and controls (n = 334) screened to exclude substance use disorders. There was evidence of association to alcohol dependence for seven adjacent markers spanning 98,000 bp in the middle and 3′‐portion of the GABRA2 gene (range of P‐values = 0.008–0.03). When the subset of the alcohol‐dependent subjects excluding those with a diagnosis of cocaine or opioid dependence or major depressive episode (n = 198) was examined, the strength of the association was increased across these 7 SNPs (range of P‐values = 0.002–0.007). Two common haplotypes in this region accounted for 90.8% of chromosomes. The more common haplotype was present in 55.6% of control group chromosomes versus 48.2% of alcohol‐dependent subjects (P = 0.007) and 45.8% of subjects with alcohol dependence but no co‐morbid drug dependence or depression (P = 0.003). These findings replicate and extend recently reported findings, which together underscore the potential contribution of polymorphic variation at the GABRA2 locus to the risk for alcohol dependence.

Genetics of two μ opioid receptor gene (OPRM1) exon I polymorphisms: population studies, and allele frequencies in alcohol- and drug-dependent subjects

FKBP5 regulates the cortisol-binding affinity and nuclear translocation of the glucocorticoid receptor. Polymorphisms at the FKBP5 locus have been associated with increased recurrence risk of depressive episodes and rapid response to antidepressant treatment. A recent study showed that FKBP5 genotypes moderated the risk of post-traumatic stress disorder (PTSD) symptoms associated with childhood maltreatment. One thousand one hundred forty-three European Americans (EAs) and 1284 African Americans (AAs) recruited for studies of the genetics of substance dependence were also screened for lifetime PTSD. Four single-nucleotide polymorphisms (SNPs) in FKBP5, rs3800373, rs9296158, rs1360780, and rs9470080, were genotyped on the complete sample. Logistic regression analyses were performed to explore the interactive effect of FKBP5 polymorphisms and childhood adversity on the risk for PTSD. After correction for multiple testing, childhood adversity significantly increased the risk for PTSD. FKBP5 genotypes were not associated with the development of the disorder. In AAs, one of the SNPs, rs9470080, moderated the risk of PTSD that was associated with childhood abuse. Without childhood adverse experiences, participants with the TT genotype of this SNP had the lowest risk for PTSD, whereas they had the highest risk for PTSD after childhood adversity exposure. In addition, in EAs, alcohol dependence was observed to interact with childhood adverse experiences, and also FKBP5 polymorphisms, to increase the risk for PTSD. This study provides further evidence of a gene × environment effect of FKBP5 and childhood abuse on the risk for PTSD in AAs. Further study is required in other populations.

Early detection of harmful alcohol consumption: comparison of clinical, laboratory, and self-report screening procedures.

The gene encoding the μ opioid receptor, OPRM1, contains at least two polymorphisms affecting protein sequence in exon 1, Ala6Val and Asp40Asn. In previous studies, each variant has been reported to be associated with some form of drug dependence. Although past reports have not been consistent, they have also not considered comparable populations. The goals of the present study were to delineate allele and haplotype frequencies of these variants in a range of populations, and in drug- or alcohol-dependent subjects deriving from some of those populations. We developed new PCR-RFLP methods to detect both of these polymorphisms and studied them in control and substance-dependent populations of African American (AA), European American (EA) and Hispanic origin, and in a series of populations differing in geographic origin (Japanese, Ethiopians, Bedouins, and Ashkenazi Jews), 891 subjects overall. We designed primers flanking the DNA segment containing both polymorphisms, each primer creating a different artificial restriction site, such that a single PCR reaction can be completed, then divided, and the PCR product digested with either of two enzymes to reveal both polymorphisms. We found that allele frequencies for both polymorphic systems were significantly different between AA and EA subjects, and there was significant heterogeneity among the more extensive set of populations. Furthermore, there were no significant differences in allele frequency by diagnosis; that is, neither polymorphism appears to be a direct risk factor for substance dependence. Finally, we demonstrated linkage disequilibrium between the two exon 1 markers, and a previously described short tandem repeat (STR) marker.

Naltrexone vs. nefazodone for treatment of alcohol dependence. A placebo-controlled trial.

This report describes the conceptual and empirical basis for the development of a screening instrument to identify persons with potentially harmful alcohol consumption. As part of a larger project sponsored by the World Health Organization (WHO), alcoholic (N = 65) and nonalcoholic (N = 187) research volunteers completed a battery of assessments that included laboratory tests, a physical examination, a diagnostic interview, personality measures, and two standard self-report screening questionnaires. The data were analyzed to evaluate the validity of diagnostic measures that could subsequently be used to develop a briefer screening test. The results of a construct validity analysis indicated that the new diagnostic measures correlated well with generally accepted alcoholism screening tests (the MAST and MacAndrew scales) and with measures of hypothetical vulnerability (e.g., sociopathy and childhood problems). Analysis of discriminant validity indicated that alcohol-specific self-report measures differentiated well between male risk groups, but were less effective in identifying high risk females. In general, alcohol-specific measures differentiated best, followed by clinical and laboratory tests and vulnerability assessments. It is concluded that no single procedure is universally suitable for the early identification of harmful drinkers. The design of a screening test will depend on the purpose of screening, the groups to be identified, the resources available and the level of cooperation to be expected from the population screened.

Genome-wide association study of alcohol dependence: significant findings in African- and European-Americans including novel risk loci

This study compared the effects of nefazodone, a serotonergic antidepressant, with the opioid antagonist naltrexone, and an inactive placebo in 183 alcohol-dependent subjects receiving weekly relapse prevention psychotherapy. Following a single-blind, placebo lead-in period, subjects were randomly assigned to receive study medication, which they took under double-blind conditions for 11 weeks. Naltrexone treatment was associated with significantly more adverse neuropsychiatric and gastrointestinal effects, poorer compliance, and a greater rate of treatment attrition. There were no reliable between-group differences in drinking behavior. These results indicate that nefazodone is not efficacious for treatment of alcohol dependence. Furthermore, the clinical utility of naltrexone seems to be limited by its adverse effects, a finding that has important implications for efforts to develop medications to treat alcohol dependence.