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Biomedical subjects

E P Noble

Publications and source records attributed to E P Noble.

At least 19 recordsLinked to original sources
PubMed2004

Advances in molecular genetics and the prevention and treatment of substance misuse: Implications of association studies of the A1 allele of the D2 dopamine receptor gene.

Substance misuse is influenced by multiple genetic and environmental factors. Recent research has identified a number of potential genetic markers of risk and those associated with drug reward substrates show particular promise. The current study reexamines the extant published data of the association between the D2 dopamine receptor (DRD2) gene minor Taq 1A (A1) allele and substance misuse risk. A series of meta-analyses was performed on 64 studies examining DRD2 A1+ allelic status and substance misuse. In addition, personality was examined as a possible endophenotype. Significant association was found between the A1 allele and severe substance dependence in both Caucasian and non-Caucasian groups. The data did not support a significant association between the A1 allele and personality features. While the specific mechanism underlying these associations requires further elucidation, this genetic marker shows promise as a marker of brain reinforcement processes. Possible ways of utilising the A1 allele to inform prevention and treatment initiatives are discussed.

Alleles↗
PubMed2002

D(2) dopamine receptor (DRD2) polymorphism is associated with severity of alcohol dependence.

The A(1) allele of the D(2) dopamine receptor (DRD2) gene has been associated with alcohol dependence. However, the expression of this allele risk on the severity of drinking behavior in patients with alcohol dependence has not been systematically explored. The present study examines the association between DRD2 A(1)(+) (A(1)/A(1) and A(1)/A(2) genotypes) and A(1)- (A(2)/A(2) genotype) allele status and key drinking parameters in alcohol-dependent patients. A sample of Caucasian adults was recruited from an alcohol detoxification unit. A clinical interview and the Alcohol Dependence Scale (ADS) questionnaire provided data on consumption, dependence, chronology of drinking and prior detoxification. A(1)(+) allele compared to A(1)- allele patients consumed higher quantities of alcohol, commenced problem drinking at an earlier age, experienced a shorter latency between first introduction to alcohol to the onset of problem drinking and had higher ADS scores. Moreover, A(1)(+) allele patients had more detoxification attempts than their A(1)- allele counterparts. In sum, alcohol-dependent patients with the DRD2 A(1) allele compared to patients without this allele are characterized by greater severity of their disorder across a range of problem drinking indices. The implications of these findings are discussed.

Adult↗
PubMed2001

GABA(A) receptor beta 3 subunit gene and psychiatric morbidity in a post-traumatic stress disorder population.

GABAergic systems have been implicated in the pathogenesis of anxiety, depression and insomnia. These symptoms are part of the core and comorbid psychiatric disturbances in post-traumatic stress disorder (PTSD). In a sample of Caucasian male PTSD patients, dinucleotide repeat polymorphisms of the GABA(A) receptor beta 3 subunit gene were compared to scores on the General Health Questionnaire-28 (GHQ). As the major allele at this gene locus (GABRB3) was G1, the alleles were divided into G1 and non-G1 groups. On the total score of the GHQ, which comprises the somatic symptoms, anxiety/insomnia, social dysfunction and depression subscales, patients with the G1 non-G1 genotype had a significantly higher score when compared to either the G1G1 genotype (alpha=0.01) or the non-G1 non-G1 genotype (alpha=0.05). No significant difference was found between the G1G1 and non-G1 non-G1 genotypes. When the G1 non-G1 heterozygotes were compared to the combined G1G1 and non-G1 non-G1 homozygotes, a significantly higher total GHQ score was found in the heterozygotes (P=0.002). These observations suggest a heterosis effect. Further analysis of GHQ subscale scores showed that heterozygotes compared to the combined homozygotes had higher scores on the somatic symptoms (P=0.006), anxiety/insomnia (P=0.003), social dysfunction (P=0.054) and depression (P=0.004) subscales. In conclusion, the present study indicates that in a population of PTSD patients, heterozygosity of the GABRB3 major (G1) allele confers higher levels of somatic symptoms, anxiety/insomnia, social dysfunction and depression than found in homozygosity.

Alleles↗
PubMed2000

The D(2) dopamine receptor A(1) allele and opioid dependence: association with heroin use and response to methadone treatment.

A total of 95 Caucasian opioid-dependent patients were followed over a one-year period in an outpatient methadone treatment program. The frequency of the TaqI A(1) allele of the D(2) dopamine receptor (DRD2) gene was 19.0% in these patients compared with 4.6% in controls free of past and current alcohol and other drug abuse and free of family history of alcohol and other drug abuse (p = 0.009). Twenty-two of these patients dropped out of the methadone program (Group A), 54 had a successful treatment (Group B), and 19 had a poor treatment (Group C) outcome. The frequency of the A(1) allele was highest in Group C (42.1%), followed by Group A (22.7%) and was lowest in Group B (9.3%). The more than fourfold higher frequency of the A(1) allele in the poor treatment outcome group compared with the successful treatment outcome group was significant (p = 0.00002). Moreover, the average use of heroin (grams/day) during the year prior to study entry was more than twice as great in patients with the A(1)(+) allele (A(1)/A(1) or A(1)/A(2) genotype) than those with the A(1)(-) allele (A(2)/A(2) genotype) (A(1)(+) allele = 0.55 +/- 0. 10, A(1)(-) allele = 0.25 +/- 0.05; p = 0.003). The results indicate that DRD2 variants are predictors of heroin use and subsequent methadone treatment outcome and suggest a pharmacogenetic approach to the treatment of opioid dependence.

Adult↗
PubMed2000

Haplotypes at the DRD2 locus and severe alcoholism.

Association studies of the minor TaqI A allele of the D(2) dopamine receptor (DRD2) gene with alcoholism have produced conflicting findings. Failure to assess alcoholics for severity of their disorder and to screen controls for substance use have been proposed as causes for the discrepant results. In the present study, five diallelic sites spanning the DRD2 gene were determined in combined Caucasian (non-Hispanic) studies of more severe alcoholics (n = 92) and controls screened for substance use (n = 85). The frequency of the minor alleles at the 3'-untranslated site (TaqI A) and two intronic sites (TaqI B and intron 6) of the DRD2 gene were each strongly associated with alcoholism. Moreover, the alcoholics compared with the controls at these three sites had a significantly higher frequency of the minor/major allele heterozygote haplotype combination (A1/A2 B1/B2 T/G) than the major allele homozygote haplotype combination (A2/A2 B2/B2 G/G). However, exon 7 and promoter alleles were not associated with alcoholism. In neither the alcoholics nor in the controls were there departures from Hardy-Weinberg equilibrium at any of the five sites examined. The most significant diallelic composite genotypic disequilibria were found when comparisons were made between TaqI A and TaqI B, TaqI A and intron 6, and TaqI B and intron 6 sites. Weaker but still significant disequilibria were observed when TaqI A and exon 7, TaqI B and exon 7, intron 6 and exon 7, and promoter and exon 7 sites were compared. However, no significant disequilibria were noted when TaqI A and promoter, TaqI B and promoter, and intron 6 and promoter sites were compared. In sum, the study found significant evidence for association of the minor alleles in the untranslated sites of the DRD2 gene and their haplotypes with the more severe alcoholic phenotype.

Adult↗
PubMed2000

Extraversion. Interaction between D2 dopamine receptor polymorphisms and parental alcoholism.

Both molecular genetic factors (the D2 dopamine receptor (DRD2) and the D4 dopamine receptor (DRD4) polymorphisms) and environmental influences of living in an alcoholic or nonalcoholic home on the personality traits of Extraversion and Neuroticism were assessed in drug-naive, young adolescent boys. There were no significant main effects of genetic or environmental factors on either Neuroticism or Extraversion as measured by the Junior Eysenck Personality Inventory (JEPI). However, a significant interaction between DRD2 (but not DRD4) alleles and environmental variables was observed on Extraversion. Specifically, children with the minor alleles of the DRD2 gene showed a significantly greater Extraversion score when living in an alcoholic than in a nonalcoholic home. In contrast, children with the major alleles of the DRD2 gene showed a trend in the opposite direction. Although the results are preliminary and pending replication, they nevertheless provide the first report of a specific gene-environment interaction involving a human personality trait.

Adolescent↗
PubMed2000

Association of D2 dopamine receptor and alcohol dehydrogenase 2 genes with Polynesian alcoholics.

Alleles of the D2 dopamine receptor (DRD2) and the alcohol dehydrogenase 2 (ADH2) genes were determined in 69 French Polynesian alcoholic patients and 57 controls matched for racial origin. Three racial groups were studied: pure Polynesians (PP), Polynesians mixed with Caucasian (PCA) ancestry and Polynesians mixed with Chinese (PCH) ancestry. DRD2 A1 allele frequencies in the alcoholics compared to their controls in these groups were: PP,.26 vs.32 (P =. 69); PCA,.44 vs.35 (P =.46); PCH,.40 vs 0.39 (P =.88). ADH2 1 allele frequencies in alcoholics compared to their controls groups were: PP, .56 vs.62 (P =.66); PCA,.75 vs.56 (P =.09); PCH,.78 vs.32 (P =.009). In the PCA group, the combination of the DRD2 A1 genotypes and the ADH2 1 homozygotes was strongly associated with alcoholism (P =. 0027). This preliminary study shows the importance of ascertaining racial ancestry in molecular genetic association studies. Moreover, it suggests that a combination of genes are involved in susceptibility to the development of alcoholism.

Adult↗
PubMed2000

Addiction and its reward process through polymorphisms of the D2 dopamine receptor gene: a review.

Since 1990, association studies have amassed strong evidence implicating the D(2) dopamine receptor (DRD2) gene in alcoholism. Specifically, the TaqI A minor (A1) allele of the DRD2 gene has been associated with alcoholism. The DRD2 gene has also been found to be involved in other substance use disorders including cocaine, nicotine and opioid dependence, and obesity. Beyond association studies, pharmacologic studies have shown reduced brain D(2) dopamine receptor numbers in A1(+) allele carriers (A1A1 and A1A2 genotypes) compared to A1(-) allele carriers (A2A2 genotype). Through a number of other approaches, different phenotypes have also been identified in subjects with the A1(+) and A1(-) alleles. These include metabolic, neurophysiological, neuropsychological, personality, stress and treatment studies. It is hypothesized that in an effort to compensate for deficiencies in the dopaminergic system, substance abusers may seek to stimulate the mesocorticolimbic circuits of the brain, long thought to be important in behavioral reward and reinforcement. In effect, one form of the DRD2 gene, the A1 allele, renders the dopaminergic system inefficient and rewards substance abuse that increases brain dopamine levels.

Alcoholism↗
PubMed2000

The DRD2 gene in psychiatric and neurological disorders and its phenotypes.

The TaqIA D2 dopamine receptor (DRD2) minor (A1) allele was first associated with severe alcoholism a decade ago. Since then, studies both confirming and not confirmnning this finding were reported. However, a meta-analysis of a large number of Caucasian alcoholics (both more severe and less severe) and controls (both assessed and unassessed for substance use disorders) revealed a significantly higher frequency (p < 10(-6)) and prevalence (p < 10(-8)) of the DRD2 A1 allele in the alcoholics. Further analysis showed that the more severe alcoholics had a 3-fold higher prevalence of the DRD2 A1 allele than the assessed controls (p < 10(-10)), whereas no difference was found between the less severe alcoholics and the unassessed controls. DRD2 exonic or promoter mutations have not yet been associated with alcoholism, although two intronic variants at the TaqIB and intron 6 sites, which are in linkage disequilibrium with the TaqIA site, were associated with this disorder. Variants of the DRD2 gene have also been associated with cocaine, nicotine and opioid dependence, obesity and gambling. It is hypothesised that the DRD2 is a reinforcement or reward gene. Although less intensively studied than substance use disorders, the DRD2 gene has been implicated in Tourette's syndrome (TS), post-traumatic stress disorder (PTSD) and certain symptoms associated with affective disorders and schizophrenia. Further, DRD2 variants have been implicated in Parkinson's disease (PD) and in iatrogenically-induced movement disorders, as well as in certain migraineurs. Phenotypic differences have been associated with DRD2 variants. These include reduced D2 dopamine receptor numbers and diminished glucose metabolism in the brain of subjects who carry the DRD2 A1 allele. In addition, phenotypic differences have been found in neurocognitive and personality characteristics, and in treatment outcome of DRD2 variants. The involvement of the DRD2 gene in certain neuropsychiatric disorders opens up the potential of a targeted pharmacogenomic approach to the prevention and treatment of these disorders.

Animals↗
PubMed1998

D2 dopamine receptor and GABA(A) receptor beta3 subunit genes and alcoholism.

As the dopaminergic and GABAergic systems have been implicated in alcohol-related behaviors, variants of the D2 dopamine receptor (DRD2) and GABA(A) receptor beta3 subunit (GABRB3) genes were determined in a population-based association study of Caucasian non-alcoholic and alcoholic subjects. In severe alcoholics, compared to non-alcoholics, a significant increase was found in the prevalence (P = 1.7 x 10(-5)) and frequency (P = 1.6 x 10(-5)) of the DRD2 minor (A1) allele. Moreover, a significant progressive increase was observed in A1 allelic prevalence (P = 3.1 x 10(-6)) and frequency (P = 2.7 x 10(-6)) in the order of non-alcoholics, less severe and severe alcoholics. In severe alcoholics, compared to non-alcoholics, a significant decrease was found in the prevalence (P = 4.5 x 10(-3)) and frequency (P = 2.7 x 10(-2)) of the GABRB3 major (G1) allele. Furthermore, a significant progressive decrease was noted in G1 allelic prevalence (P = 2.4 x 10(-3)) and frequency (P = 1.9 x 10(-2)) in non-alcoholics, less severe and severe alcoholics, respectively. In sum, in the same population of non-alcoholics and alcoholics studied, variants of both the DRD2 and GABRB3 genes independently contribute to the risk for alcoholism, with the DRD2 variants revealing a stronger effect than the GABRB3 variants. However, when the DRD2 and the GABRB3 variants are combined, the risk for alcoholism is more robust than when these variants are considered separately.

Adult↗
PubMed1998

D2 and D4 dopamine receptor polymorphisms and personality.

The relationship of various dimensions of temperament, measured by the Tridimensional Personality Questionnaire (TPQ), to polymorphisms of the D2 dopamine receptor (DRD2) and D4 dopamine receptor (DRD4) genes was determined in 119 healthy Caucasian boys who had not yet begun to consume alcohol and other drugs of abuse. Total Novelty Seeking score of the TPQ was significantly higher in boys having, in common, all three minor (A1, B1, and Intron 6 1) alleles of the DRD2 compared to boys without any of these alleles. Boys with the DRD4 7 repeat (7R) allele also had a significantly higher Novelty Seeking score than those without this allele. However, the greatest difference in Novelty Seeking score was found when boys having all three minor DRD2 alleles and the DRD4 7R allele were contrasted to those without any of these alleles. Neither the DRD2 nor the DRD4 polymorphisms differentiated total Harm Avoidance score. Whereas subjects having all three minor DRD2 alleles had a significantly higher Reward Dependence 2 (Persistence) score than subjects without any of these alleles, no significant difference in this personality score was found between subjects with and without the DRD4 7R allele. In conclusion, DRD2 and DRD4 polymorphisms individually associate with Novelty Seeking behavior. However, the combined DRD2 and DRD4 polymorphisms contribute more markedly to this behavior than when these two gene polymorphisms are individually considered.

Adolescent↗
PubMed1998

The D2 dopamine receptor gene: a review of association studies in alcoholism and phenotypes.

The role of the D2 dopamine receptor (DRD2) gene in alcoholism and other substance use disorders has come under intense investigation since the minor TaqI A (A1) allele of the DRD2 gene was first reported to be associated with alcoholism. In a meta-analysis of 15 US and international studies of European (non-Hispanic) Caucasians, consisting of 1015 alcoholics (more severe and less severe) and 898 controls (unassessed and assessed for alcoholism), alcoholics had a higher prevalence (p < 10(-7)) and frequency (p < 10(-5)) of the A1 allele than controls. The prevalence of the A1 allele was 1.5-fold higher in more severe than less severe alcoholics (p < 10(-4)), whereas unassessed controls had a twofold higher prevalence of the A1 allele than assessed controls (p < 10(-4)). Whereas more severe alcoholics had a threefold higher A1 allelic prevalence than assessed controls (p < 10(-10)), A1 allelic prevalence was virtually identical in less severe alcoholics and in unassessed controls. The A1 allele has also been associated with other drug problems including cocaine, nicotine, and polysubstance abuse. Furthermore, the minor TaqI B (B1) allele of the DRD2 gene has been associated with alcoholism and psychostimulant (cocaine, amphetamine) abuse. Beyond association studies, phenotypic differences exist between genotypes containing the TaqI A minor (A1A1 and A1A2) and major (A2A2) alleles of the DRD2. These different phenotypes have been identified through a number of approaches, including pharmacological, neurophysiological, neuropsychological, stress, personality, metabolic, and treatment studies. In conclusion, the present review suggests that the type of alcoholics and the nature of controls used are among critical factors in DRD2 association studies in alcoholism. Intronic mutations in both the 3'(TaqI A) and 5'(TaqI B) regions of the DRD2 associate with alcoholism and other drug use disorders. The identification of phenotypes of DRD2 genotypes suggests that the observed intronic DRD2 mutations may have functional consequences that predispose individuals to a variety of substance use disorders.

Alcoholism↗
PubMed1997

D2 dopamine receptor polymorphism and brain regional glucose metabolism.

Positron emission tomography (PET) studies have shown decreased glucose metabolism in brain regions of detoxified alcoholics and cocaine abusers. However, it is not clear whether this decrease is due to chronic drug abuse or a pre-existing condition. Molecular genetic studies have found an association of the D2 dopamine receptor (DRD2) A1 allele with alcoholism and drug abuse. Moreover, reduced central dopaminergic function has been suggested in subjects who carry the A1 allele (A1+) compared with those who do not (A1-). In the present study, using 18F-deoxyglucose, regional glucose metabolism was determined in healthy nonalcohol/nondrug-abusing subjects with the A1+ or A1- allele. The mean relative glucose metabolic rate (GMR) was significantly lower in the A1+ than the A1- group in many brain regions, including the putamen, nucleus accumbens, frontal and temporal gyri and medial prefrontal, occipito-temporal and orbital cortices. Decreased relative GMR in the A1+ group was also found in Broca's area, anterior insula, hippocampus, and substantia nigra. A few brain areas, however, showed increased relative GMR in the A1+ group. Since polymorphism of the DRD2 gene is commonly observed in humans, the importance of differentiating A1+ and A1- alleles subjects in PET studies is suggested.

Adult↗
PubMed1997

Association of the D2 dopamine receptor A1 allele with alcoholism: medical severity of alcoholism and type of controls.

D2 dopamine receptor (DRD2) A1 allele frequency was determined in alcoholics of varying medical severity from three different inpatient settings and in various controls. A1 frequency was .15 in 68 alcoholics in a detoxification unit (group A), .19 in 90 alcoholics in a rehabilitation unit (group B), and .31 in 43 alcoholics in a gastroenterology unit (group C). Group C had a higher A1 frequency than group B (p = .045) or group A (p = .005) alcoholics. In 46 controls (group D), A1 frequency was .18. In subsets of these controls, A1 frequency was .14 in 39 subjects with a negative family history (FH-) of alcoholism (group E), .06 in 34 subjects without previous hazardous alcohol consumption (group F), and .05 in 30 subjects with FH- and without previous hazardous alcohol consumption (group G). A1 frequency was significantly higher in group C alcoholics than group F (p = .0002) or group G (p = .0002) controls; however, no A1 frequency difference was found among group A alcoholics and any of the control groups. The severity of alcoholism and the type of controls used are important determinants of DRD2 A1 allele association with alcoholism.

Alcohol Drinking↗
PubMed1997

D2 dopamine receptor A1 allele in Alzheimer disease and aging.

BACKGROUND: The apolipoprotein E4 (APOE*4) allele is a major risk factor for the common forms of late-onset Alzheimer disease (AD), but does not account for all the genetic variation in late-onset AD; hence, other genetic markers must be examined. The D2 dopamine receptor (DRD2) A1 allele is associated with abnormal brain function and decreased DRD2s. These receptors are decreased in hippocampus and amygdala in AD, and allele frequencies may vary with age. OBJECTIVE: To study APOE and DRD2 genotypes in patients with AD and cognitively intact controls of varying ages. DESIGN: The DRD2 and APOE genotypes were examined in 832 unrelated white subjects, including 554 patients with AD (486 sporadic; 68 familial) and 278 controls. Logistic regressions tested A1 allele effects on disease status and age, and DRD2 linkage with AD was investigated in 60 families with late-onset AD. SETTING: University medical centers. SUBJECTS: Patients (mean +/- SD age, 74.6 +/- 8.1 years; range, 52-98 years) had probable AD, according to standard consensus diagnostic criteria; controls (mean +/- SD age, 69.2 +/- 8.6 years; range, 50-93 years) were cognitively intact. MAIN OUTCOME MEASURES: Disease status, age, and DRD2 linkage with AD. RESULTS: No association between the DRD2 and APOE alleles was found, and the presence of the A1 allele did not increase the risk for AD. There was also no evidence of linkage between DRD2 and AD. Age analyses, including both patients and controls, indicated a decrease in A1 allele frequency with age. CONCLUSIONS: The A1 allele does not contribute to AD risk, alone or in combination with the APOE*4 allele. The DRD2 A1 allele frequencies decrease with age in both patients and controls. Thus, studies of DRD2 disease association need to control for age.

Aged↗
PubMed1997

The D2 dopamine receptor (DRD2) gene and family stress; interactive effects on cognitive functions in children.

TaqI A D2 dopamine receptor (DRD2) alleles, family stress, and cognitive markers, including visuospatial ability (Benton's Line Orientation) and event-related potentials (P300 amplitude and latency), were obtained in preadolescent boys of alcoholic and nonalcoholic fathers. In the presence of the DRD2 minor allele (A1+), the Family Stress score negatively correlated with the Line Orientation score and P300 amplitude. No significant correlations were found in boys lacking this allele (A1-). The interaction of the A1+ allele and the Family Stress score produced significant regression coefficients for both Line Orientation score (p = .002) and P300 amplitude (p = .04). Together, these two cognitive markers account for 37% of the variance in the Family Stress score of 47 A1 allele boys (p = .0002) but less than 1% in 71 A1- allele boys (p > .9). This provides the first evidence of a specific gene-environment interaction involving human cognitive functioning.

Adolescent↗