Association of dopamine-related gene alleles, smoking behavior and decline in FEV1 in subjects with COPD: findings from the lung health study.

Cigarette smoking is the major risk factor for chronic obstructive pulmonary disease (COPD). Specific dopamine related gene alleles have previously been found to be associated with smoking initiation, maintenance and cessation. We investigated the association between specific dopamine related gene alleles and both change in smoking behavior and lung function change over time in individuals with mild-to-moderate COPD. Subjects included a subset of participants in the Lung Health Study (LHS), a smoking intervention study in smokers with mild to moderate COPD. Smoking status was determined and lung function performed at baseline and annually for 5 years. In post-hoc analyses, we assessed the association of the dopamine receptor (DRD2) TaqI A1(+) allele (A1A1, A1A2 genotypes) and A1(-) allele (A2A2 genotype), and the dopamine transporter (DAT) 9R(+) allele (9R9R and 9R10R genotypes) and 9R(-) allele (10R10R genotype) with both changes in smoking status and lung function in a subset of LHS subjects. No significant associations were noted between variants in these genes and success in smoking cessation. However, in exploratory analyses that did not adjust for multiple comparisons, sustained male (but not female) quitters with the DRD2 A1(-) allele and/or the DAT 9R(+) allele showed an accelerated decline in FEV(1) similar to that of continuing smokers over 5 years after quitting smoking. These preliminary findings suggest that dopamine-related genes may play a role in the progression of COPD, at least in the subset of male ex-smokers whose disease continues to progress despite sustained quitting, and warrants additional confirmatory and mechanistic studies.

D2 dopamine receptor (DRD2) gene, P300, and personality in children of alcoholics.

The D2 dopamine receptor (DRD2) gene has been associated with alcoholism and other drug use disorders. Reduced P300 amplitude has been noted in individuals with psychiatric disorders. Personality variables are also associated with reduced P300 amplitude. The current study was conducted to determine whether variants of the DRD2 would show differential relationships among P300 amplitude and personality traits. The study consisted of 101 adolescent children of alcoholics; 39 carried the A1(+) genotype (A1A1, A1A2) and 62 carried the A1(-) genotype (A2A2). The A1(+) genotype group had higher IQ and Self-Directedness scores than the A1(-) genotype group. As predicted, the negative relationship between Novelty Seeking and Harm Avoidance was present in A1(-) but not A1(+) participants. Additionally, in A1(+) but not in A1(-) participants, there was a negative relationship between Novelty Seeking and Self-Directedness and a positive relationship between P300 amplitude and Cooperativeness. The results suggest that in adolescent children of alcoholics, dopaminergic genetic determinants are critical modifiers of the relationship between neurocognitive and personality endophenotypes proposed as vulnerability markers for substance use disorders.

The A1 allele of the D2 dopamine receptor gene region, alcohol expectancies and drinking refusal self-efficacy are associated with alcohol dependence severity.

Psychological risk and genetic risk for alcohol dependence are rarely examined in concert. The current study used path analysis (via structural equation modelling) to explore the relationship between the A(1) allele of the D2 dopamine receptor DRD2 gene region, age of problem drinking onset, alcohol expectancy and drinking refusal self-efficacy towards alcohol consumption and dependence severity. One hundred and forty-three (93 male, 50 female) alcohol dependent inpatients provided an extensive clinical history, including age of onset of problem drinking and quantity and frequency of alcohol consumption. The Drinking Expectancy Profile and the Alcohol Dependence Scale were completed, and 10 milliliters of blood were obtained for genetic analysis. The results showed that the posited model fitted the data set well and support the pattern of direct (allele status to drinking) and indirect (allele status influenced by psychosocial variables) relationships hypothesised for the model. A formal test of mediation showed some support for a psychosocial mediational model. The results are discussed in terms of a possible developmental trajectory that involves both genetic risk that influences brain dopamine activity and reinforcement expectancies that both operate via diminished drinking refusal self-efficacy. The prevention and treatment possibilities that arise from understanding this trajectory are examined.

Heavy nicotine and alcohol use in alcohol dependence is associated with D2 dopamine receptor (DRD2) polymorphism.

Cigarette smoking in those who are alcohol dependent is associated with higher morbidity and mortality. The A1 allele of the D2 dopamine receptor (DRD2) gene has been independently associated with alcohol and nicotine dependence. Whether this polymorphism is associated with nicotine dependence in those who are also alcohol dependent has not been investigated. Subjects were 84 (61 males; 23 females) Caucasian DSM IV diagnosed nicotine- and alcohol-dependent subjects sampled from consecutive admissions to a hospital alcohol detoxification ward. Data were obtained through standardised measures of nicotine and alcohol consumption and dependence severity. A1+ allelic (A1/A1 or A1/A2 genotype) compared to A1- allelic (A2/A2 genotype only) patients were characterised by higher levels of alcohol and cigarette consumption. A1+ allelic patients reported greater alcohol dependence severity, but not nicotine dependence severity. When the combined nicotine and alcohol dose was examined, A1+ allelic patients consumed significantly more of these drugs than their A1- allelic counterparts.

D2 dopamine receptor gene polymorphism: paroxetine and social functioning in posttraumatic stress disorder.

This study examined whether allelic status of the D2 dopamine receptor (DRD2) gene was associated with response to a selective serotonin reuptake inhibitor, paroxetine, in the treatment of posttraumatic stress disorder (PTSD). Sixty-three Caucasian war veterans with combat-related PTSD were treated with paroxetine for 8 weeks. Patients were assessed at baseline and at follow-up using the General Health Questionnaire-28 (GHQ). TaqI A DRD2 alleles were determined by PCR. Before paroxetine treatment, patients with the DRD2 A1+ allele (A1A2 genotype) compared to those with the A1- allele (A2A2 genotype) had higher total GHQ psychopathological scores (P=0.040) and higher GHQ subscale scores for anxiety/insomnia (0.046), social dysfunction (P=0.033) and depression (P=0.011). In an intention-to-treat analysis, paroxetine was associated with significant improvement in total GHQ scores (P=0.014) and in the factor scores of social dysfunction (P=0.033), anxiety (P=0.009) and depression (P=0.026). Furthermore, there was a significant allele by time interaction on the social dysfunction scale, with A1+ allelic patients showing significant improvement in social functioning compared to A1- allelic patients (P=0.031), an effect independent of changes in depression or anxiety. This suggests changes in social functioning induced by paroxetine may be, in part, mediated via D2 dopamine receptors. The DRD2 A1 allele may prove to be a useful marker to assist clinicians in predicting which patients with PTSD are likely to obtain improvements in social functioning with paroxetine treatment.

Genetic, personality, and environmental predictors of drug use in adolescents.

During adolescence there is a significant increase in risk-taking behavior, including experimenting with alcohol and drugs, which can lead to drug dependence. A new hypothesis regarding the genetic mechanisms that lead to drug use is tested using adolescent Caucasian children of alcoholics (57 males, 54 females; mean age = 14.5 years) data. Variables included in the study were dopaminergic genes (ANKK1 TaqI A, DRD2 C957T, DRD4 7R, COMT Val/Met substitution, and SLC6A3 9R) and a GABAergic gene (GABRB3), all combinations of genes, a count of the number of hypodopaminergic genotypes, personality traits, neurocognitive factors, depressive symptoms, and environmental factors. Separate predictive models were found for males and females. Hypodopaminergic functioning predicted drug use in males; however, in females, a deleterious environment was the salient predictor. This preliminary study suggests that it is possible to identify children at risk for problematic drug use prior to the onset of drug dependence.