Plasma Dopamine-beta-hydroxylase Activity Research Articles

Nicotine dependence as a moderator of genetic influences on smoking cessation treatment outcome

BackgroundGenetic influences on smoking cessation treatment outcome may be affected by pretreatment patient characteristics. Nicotine dependence is arguably the most salient clinical factor in smoking cessation. Methods: In this secondary analysis of clinical trial data (N=793), we examined nicotine dependence severity as a moderator of the effects of 1198 single nucleotide polymorphisms (SNPs) in 53 biologically-relevant gene regions on smoking cessation outcomes. P-values were adjusted to account for multiple correlated SNPs within a gene region; corrected system-wide significance was 5×10−4. Results: SNP×nicotine dependence interactions reached region-wide significance for several SNPs in the Dopamine Beta Hydroxylase (DBH) locus (0.0005<Adjusted-P<0.05), including rs1541333, which reached system-wide significance for predicting end of treatment (EOT) abstinence (Adjusted-P=0.0004). A haplotype including 6 DBH SNPs predicted abstinence at EOT (OR=1.7, P=0.001) and 6-month follow-up (OR=1.6, P=0.008) in those with high nicotine dependence (n=526) but not in those with low dependence (n=227). The DBH signal observed here may be distinct from a previously reported genome-wide significant signal for former smoking status and from the principal haplotype associated with plasma dopamine beta-hydroxylase activity. A haplotype within the Chromosome 15 Nicotinic Acetylcholine Receptor gene region predicted abstinence at EOT in those with high (OR=2.0, P=0.0004) but not low (P=0.6) dependence in post hoc analyses. Conclusions: Considering pre-treatment nicotine dependence level may optimize the prediction of genetic influences on cessation outcomes. If replicated, results like these may inform prognosticative genomic screening panels designed to identify smokers at high risk of relapse when coupled with severe nicotine dependence.

Association of the dopamine β‐hydroxylase 19 bp insertion/deletion polymorphism with positive symptoms but not tardive dyskinesia in schizophrenia

Overactivity of dopaminergic neurotransmission is a putative mechanism of tardive dyskinesia (TD). Dopamine beta-hydroxylase (DBH) is a key enzyme in the conversion of dopamine to norepinephrine, and plasma DBH activity is altered in TD patients. This study examined whether the functional DBH 5'-Ins/Del polymorphism was associated with TD severity in Chinese patients with schizophrenia. We compared the rate of this polymorphism in patients with (n = 312) and without TD (n = 435), and healthy controls (n = 625). The severity of TD was assessed using the Abnormal Involuntary Movement Scale (AIMS) and psychopathology using the Positive and Negative Syndrome Scale (PANSS). There were no significant differences in the distribution of the allele and genotype frequencies between the patients and controls, or between the patients with and without TD. Also, there was no significant difference in the AIMS total score between the three genotype groups. However, the PANSS positive symptom subscore was significantly higher in patients with Del/Del genotype (13.2 ± 5.2) than those with Ins/Del (11.2 ± 4.9) and Ins/Ins (11.1 ± 3.1) genotypes (both p < 0.05). These results suggest that although the DBH 5'-Ins/Del polymorphism was not associated with susceptibility to TD in patients with schizophrenia, it might be related to positive symptoms of schizophrenia.

Positive association between −1021TT genotype of dopamine beta hydroxylase gene and progressive behavior of injection heroin users

By balancing the ratios of dopamine and norepinephrine, dopamine beta hydroxylase (DBH) plays an important role in brain reward circuit that is involved with behavioral effects of heroin addiction. DBH −1021C/T (rs1611115) is a functional variant with strong correlation with plasma DBH activity and several nerval and psychic disorders. In the present study, we have collected 333 male cases with heroin addiction and 200 male healthy controls to explore the role of −1021C/T in heroin addiction. There is no evidence of association between −1021C/T and heroin addiction on both genotype and allele levels (P>0.05). In the injection subgroup of cases, −1021TT carriers have longer heroin addiction time (P<0.001) and higher dosage of self-administered heroin (P=0.045) than carriers with −1021CC or −1021CT, suggesting that patients with TT genotype are likely to have more progressive style of heroin users with injection route. In conclusion, our results support −1021TT genotype may be implicated with a more progressive nature of heroin addiction, although DBH −1021C/T is unlikely to be involved in the risk of heroin addiction.

Genotype-independent decrease in plasma dopamine beta-hydroxylase activity in Alzheimer's disease

The noradrenergic system is involved in the etiology and progression of Alzheimer's disease (AD) but its role is still unclear. Dopamine beta-hydroxylase (DBH) as a catecholamine-synthesizing enzyme plays a central role in noradrenaline (NA) synthesis and turnover. Plasma DBH (pDBH) activity shows wide inheritable interindividual variability that is under genetic control. The aim of this study was to determine pDBH activity, DBH (C-970T; rs1611115) and DBH (C1603T; rs6271) gene polymorphisms in 207 patients with AD and in 90 healthy age-matched controls. Plasma DBH activity was lower, particularly in the early stage of AD, compared to values in middle and late stages of the disease, as well as to control values. Two-way ANOVA revealed significant effect of both diagnosis and DBH (C-970T) or DBH (C1603T) genotypes on pDBH activity, but without significant diagnosis×genotype interaction. No association was found between AD and DBH C-970T (OR=1.08, 95% CI 1.13-4.37; p=0.779) and C1603T (OR=0.89; 95% CI 0.36-2.20; p=0.814) genotypes controlled for age, gender, and ApoE4 allele. The decrease in pDBH activity, found in early phase of AD suggests that alterations in DBH activity represent a compensatory mechanism for the loss of noradrenergic neurons, and that treatment with selective NA reuptake inhibitors may be indicated in early stages of AD to compensate for loss of noradrenergic activity in the locus coeruleus.

The effects of cadmium ions on blood pressure, dopamine-beta-hydroxylase activity and on the responsiveness of in vivo preparations to sympathetic nerve stimulation, noradrenaline and tyramine.

Changes in sympathetic nervous function of the rat caused by acute and chronic treatment with cadmium ((Cd2+) have been studied in vivo by measurement of changes in blood pressure and plasma dopamine-beta-hydroxylase (DBH) activity. In anaesthetized animals, acute injection of Cd2+ (0.1-1 microM) caused an initial fall followed by a rise in both diastolic and systolic blood pressure, plasma DBH activity increased in a dose-dependent manner. Animals subjected to repeated treatment with Cd2+ (0.5, 1 microM) daily for 12 days became markedly hypertensive, the increases in the systolic pressure being greater than those seen in the diastolic pressure. In pithed animals the blood pressure responses of the treated animals to electrical stimulation of the lower sympathetic outflow (T10-L1) and tyramine injection (35, 70, 140 nmol kg-1) were markedly decreased, whilst responses to low doses of noradrenaline (NA) (7, 15, 30 nmol kg-1) were potentiated compared with untreated animals. In addition, plasma DBH activities following sympathetic outflow stimulation and tyramine administration were markedly increased and decreased respectively compared with untreated controls. The data suggest that a correlation exists between changes in sympathetic nervous function and the induction of hypertension caused by Cd2+.

Psychose et traumatisme psychique. Pour une articulation théorique des symptômes psycho-traumatiques et psychotiques chroniques

The co-occurrence between post-traumatic symptoms and psychotic symptoms is well described in the immediate suites of a trauma but can also be chronic. This symptomatic co-occurrence, rarely studied in the literature, is often approached under the sole angle of a primary post-traumatic stress disorder (PTSD) or of a primary psychosis, without federative will to unify the psychotic and post-traumatic symptoms within the same nosological framework. Individuals with schizophrenia or schizoaffective disorder report higher rates of trauma and assault than the general population. High rates of PTSD have been noted in severe mental illness cohorts. Psychotic phenomena may be a relatively common manifestation in patients with chronic PTSD. The purpose of this paper is to expose the various theorical psychopathological aspects between the symptoms of psychosis and PTSD. In populations of veterans, positive and negative symptoms of psychosis in PTSD are described as delusional thoughts and hallucinations often combat-specific. When a PTSD becomes established at a subject to the personality of neurotic structure, the intensity of the PTSD's symptoms lead to a psychotic expression which constitutes a factor of seriousness. Besides, PTSD often induces a risk of substance use disorder supplying psychotic symptoms. Cannabis increases the hallucinations, cocaine strengthens an underlying paranoid tone, and alcohol implies withdrawal hallucinosis. Moreover, such consumption could be a risk factor for the future development of chronic psychosis. From another point of view, by basing themselves on the plasma dopamine beta-hydroxylase activity, some authors made the analogy between psychotic major depression and PTSD with psychotic features (also characterized as a distinct psychotic subtype of PTSD). However, other studies found no correlation between PTSD with psychotic features and family predisposition for schizophrenia or schizoaffective disorder. The determination of the structure of personality seems fundamental in the understanding of the symptoms. A personality of psychotic structure increases the risk of traumatization and PTSD. At the same time, the fragility of this structure causes an increased sensitivity to the trauma, which takes on a particular echo. Moreover, a trauma can test a latent psychotic structure to reveal its existence. The experience of psychosis may be traumatic in itself for patients with, notably, seclusion and sedation during hospitalization. Lastly, the symptoms of this post-traumatic psychosis will be differentiated from neurological confusion caused by a traumatic brain injury. Clinicians often fail to screen routinely for trauma and PTSD symptoms in patients with severe mental illness because few systematic guidelines exist for the identification and treatment of this comorbidity. The links between psychotic and psycho-traumatic symptoms are complex and multidirectional; this co-occurrence is a factor of seriousness. The clinician, while paying attention to these symptoms, has to distinguish the structure of the personality of the subject to articulate the psychotherapy and the pharmacological treatment. Further investigational studies may determine whether antipsychotics will enhance treatment response in PTSD patients with psychotic features.

Human dopamine beta-hydroxylase (DBH) regulatory polymorphism that influences enzymatic activity, autonomic function, and blood pressure.

Dopamine beta-hydroxylase (DBH) plays an essential role in catecholamine synthesis by converting dopamine into norepinephrine. Here we systematically investigated DBH polymorphisms associated with enzymatic activity as well as autonomic and blood pressure (BP)/disease phenotypes in vivo. Seventy genetic variants were discovered at the locus; across ethnicities, much of the promoter was spanned by a 5' haplotype block, with a larger block spanning the promoter in whites than blacks. DBH secretion was predicted by genetic variants in the DBH promoter, rather than the amino acid coding region. The C allele of common promoter variant C-970T increased plasma DBH activity, epinephrine excretion, the heritable change in BP during environmental stress in twin pairs, and also predicted higher basal BP in three independent populations. Mutagenesis and expression studies with isolated/transfected DBH promoter/luciferase reporters in chromaffin cells indicated that variant C-970T was functional. C-970T partially disrupted consensus transcriptional motifs for n-MYC and MEF-2, and this variant affected not only basal expression, but also the response to exogenous/co-transfected n-MYC or MEF-2; during chromatin immunoprecipitation, these two endogenous factors interacted with the motif. These results suggest that common DBH promoter variant C-970T plays a role in the pathogenesis of human essential hypertension: common genetic variation in the DBH promoter region seems to initiate a cascade of biochemical and physiological changes eventuating in alterations of basal BP. These observations suggest new molecular strategies for probing the pathophysiology, risk, and rational treatment of systemic hypertension.

Association between migraine and a functional polymorphism at the dopamine β-hydroxylase locus

Migraine is a common neurological disorder with a significant genetic component. Although a number of linkage and association studies have been undertaken, the number and identity of all migraine susceptibility genes has yet to be defined. The existence of dopaminergic hypersensitivity in migraine has been recognised on a pharmacological basis and some studies have reported genetic association between migraine and dopamine-related gene variants. Our laboratory has previously reported association of migraine with a promoter STR marker in the dopamine beta hydroxylase (DBH) gene. In the present study, we analysed two additional DBH markers in two independent migraine case-control cohorts. These two markers are putative functional SNPs, one within the promoter (-1021C-->T) and another SNP (+1603C-->T) in exon 11 of the DBH gene. The results showed a significant association for allelic and genotypic frequency distribution between the DBH marker in the promoter and migraine in the first (P = 0.004 and P = 0.012, respectively) and the second (P = 0.013 and P = 0.031, respectively) tested cohorts. There was no association observed between either genotype and/or allelic frequencies for the DBH marker located in exon 11 and migraine (P > or = 0.05). The promoter DBH marker, reported associated with migraine in this study, has been shown to affect up to 52% of plasma DBH activity. Varying DBH activity levels have been postulated to be involved in migraine process with an increase of dopamine, resulting from a lower DBH activity shown positively correlated with migraine severity. It is plausible that the functional promoter variant of DBH may play a role in the migraine disorder.

Polymorphisms in the DBH gene promoter region and affective temperaments in healthy volunteers

Event Abstract Back to Event Polymorphisms in the DBH gene promoter region and affective temperaments in healthy volunteers Gabriella Eördegh1*, Tibor Rudisch1, Anna Juhasz1, Agnes Rimanoczy1, Ambrus Z. Kovacs1, Edina Papp1 and Zoltan Janka1 1 Department of Psychiatry, Albert Szent-Györgyi Medical and Pharmaceutical Center, University of Szeg, Hungary Dopamine-beta-hydroxylase (DBH) is an enzyme that converts dopamine to noradrenaline. The plasma DBH activity seems to be correlated with human behaviour and psychological traits. Many types of DBH polymorphisms were investigated and the DBH-1021CT polymorphism was found to be associated with the plasma DBH activity. The association between the plasma DBH activity and alcoholism, smoking, attention deficit hyperactivity disorder (ADHD), antisocial behaviour, and the scores on Minnesota Multiphasic Personality Inventory (MMPI), Eysenck Personality Questionnaire (EPQ) and Cloninger’s temperament scales was investigated in several studies. In order to examine whether there is any association between the temperament types and the DBH-1021CT polymorphism we applied in our study a temperament personality inventory, the Temperament Evaluation of Memphis, Pisa, Paris and San Diego Autoquestionnaire (TEMPS-A). The investigation was carried out in a sample of 140 unrelated Caucasian healthy, young adult volunteers in both genders (107 females and 33 males). Four of the five temperament scales indicated significant difference between the persons with at least one DBH-1021 T allel and the CC homozygotes. The results of the T-carrier individuals were significant lower in the depressive, the cyclothymic and the anxious temperament scales, while in the hyperthymic scale the CC homozygotes had significant lower mean score. However, the irritable temperament scale demonstrated no difference between the two investigated groups. Our findings support the previous suggestion that the DBH-1021CT polymorphism correlates with personality traits. This work was supported by grants from the Hungarian Ministry of Health (ETT 198 04/ 2006) and the Hungarian Scientific Research Fund (OTKA T 046152/2004). Conference: 12th Meeting of the Hungarian Neuroscience Society, Budapest, Hungary, 22 Jan - 24 Jan, 2009. Presentation Type: Poster Presentation Topic: Behavioural neuroscience Citation: Eördegh G, Rudisch T, Juhasz A, Rimanoczy A, Kovacs AZ, Papp E and Janka Z (2009). Polymorphisms in the DBH gene promoter region and affective temperaments in healthy volunteers. Front. Syst. Neurosci. Conference Abstract: 12th Meeting of the Hungarian Neuroscience Society. doi: 10.3389/conf.neuro.01.2009.04.229 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 09 Mar 2009; Published Online: 09 Mar 2009. * Correspondence: Gabriella Eördegh, Department of Psychiatry, Albert Szent-Györgyi Medical and Pharmaceutical Center, University of Szeg, Szeged, Hungary, nagyneegabi@freemail.hu Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Gabriella Eördegh Tibor Rudisch Anna Juhasz Agnes Rimanoczy Ambrus Z Kovacs Edina Papp Zoltan Janka Google Gabriella Eördegh Tibor Rudisch Anna Juhasz Agnes Rimanoczy Ambrus Z Kovacs Edina Papp Zoltan Janka Google Scholar Gabriella Eördegh Tibor Rudisch Anna Juhasz Agnes Rimanoczy Ambrus Z Kovacs Edina Papp Zoltan Janka PubMed Gabriella Eördegh Tibor Rudisch Anna Juhasz Agnes Rimanoczy Ambrus Z Kovacs Edina Papp Zoltan Janka Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Dopamine-beta hydroxylase polymorphism and cocaine addiction

Cocaine addiction involves a number of medical, psychological and social problems. Understanding the genetic aetiology of this disorder will be essential for design of effective treatments. Dopamine-beta hydroxylase (DbH) catalyzes the conversion of dopamine to norepinephrine and could, therefore, have an influence on both cocaine action and the basal sensitivity of neurotransmitter systems to cocaine. Recently, the -1021C>T polymorphism have been found to strongly correlated with individual variation in plasma DbH activity. To test the influence of this polymorphism on the susceptibility of cocaine addiction, we decided to genotype it in a sample of 689 cocaine addicts and 832 healthy individuals. Genotypic and allelic analyses did not show any evidence of association with cocaine addiction, even after correcting for the effect of population stratification and other possible confounders. Our results do not support a major role of the -1021C>T polymorphism or the gene itself in the development of cocaine addiction but further examination of other variants within this gene will be necessary to completely rule out an effect.

Correlation of Plasma Dopamine β-hydroxylase Activity with Polymorphisms in DBH Gene: A Study on Eastern Indian Population

Plasma dopamine beta-hydroxylase activity (plDbetaH) is tightly regulated by the DBH gene and several genetic polymorphisms have been found to independently exert their influence. In the present investigation, association of four DBH polymorphisms, DBH-STR, rs1611115, rs1108580, and rs2519152 with plDbetaH was examined in blood samples from 100 unrelated individuals belonging to the state of West Bengal, Eastern India. Genotypes obtained after PCR amplification and restriction digestion were used for statistical analyses. plDbetaH was measured using a photometric assay and its correlation with the genetic polymorphisms was analyzed using analysis of variance and linear regression. Moderate linkage disequilibrium (LD) was observed between DBH-STR and rs1611115, while rs1108580 and rs2519152 were in strong LD. 'T' allele of rs1611115 showed strong negative correlation with plDbetaH, whereas DBH-STR, rs1108580 and rs2519152 had no major effect. Four haplotypes showed significant influence on plDbetaH. This is the first report on the effect of genetic polymorphisms on plDbetaH from the Indian sub-continent. rs1611115 was the only polymorphism that showed substantial control over plDbetaH. Other polymorphisms which did not show individual effects could possibly be part of larger haplotype blocks that carry the functional polymorphisms controlling plDbetaH.

Dopamine beta‐hydroxylase (DBH) activity and ‐1021C/T polymorphism of DBH gene in combat‐related post‐traumatic stress disorder

The roles of dopamine (DA) and norepinephrine (NE) in posttraumatic stress disorder (PTSD) are unclear. The aim of the study was to determine plasma dopamine beta-hydroxylase (DBH) activity and DBH-1021C/T gene polymorphism in combat veterans with (N = 133) or without (N = 34) chronic PTSD. Similar frequencies in genotype or allele distribution were found between veterans with or without PTSD. War veterans with PTSD had lower DBH activity, associated with the DBH-1021C/T variant in DBH genes, than veterans without PTSD. A significantly lower plasma DBH activity was found in combat veterans with PTSD carrying the CC genotype as compared to veterans without PTSD carrying the corresponding genotype. Since both groups were exposed to the same trauma, it is possible that a pre-existing trait difference in regulation of NE function contributed to a differential vulnerability to develop PTSD, or that the regulation of DBH expression was different in response to trauma. The results suggest that that genotype-controlled measurement of plasma DBH activity might be used as a potential biological marker of the response to trauma, and that further studies of DBH and other loci related to DA and NA in PTSD are warranted.

Lack of significant association between −1021C→T polymorphism in the dopamine beta hydroxylase gene and attention deficit hyperactivity disorder

Recent trends in medications for attention deficit hyperactivity disorder (ADHD) suggest that norepinephrine (NE) deficiency may contribute to the disease etiology. Dopamine beta hydroxylase (DBH) is the key enzyme which converts dopamine to NE and since DBH gene is considered a major quantitative trait locus for plasma DBH activity, genetic polymorphism may lead to altered NE neurotransmission. Several polymorphisms including a 5′ flanking −1021C→T polymorphism, was reported to be associated with changed DBH activity and an association between −1021C→T polymorphism with ADHD was observed in Han Chinese children. We have carried out family-based studies with three polymorphisms in the DBH gene, −1021C→T polymorphism, exon 2*444g/a and intron 5 TaqI RFLP, to explore their association with Indian ADHD cases. Allele and genotype frequency of these polymorphisms in ADHD cases were compared with that of their parents and a control group. Haplotypes obtained were analyzed for linkage disequilibrium (LD). Haplotype-based haplotype relative risk analysis and transmission disequilibrium test showed lack of significant association between transmission of the polymorphisms and ADHD. A haplotype comprising of allele 1 of all polymorphisms showed a slight positive trend towards transmission from parents to ADHD probands. Strong LD was observed between *444g/a and TaqI RFLP in all the groups. However, low D′ values and corresponding log of odds scores in the control group as compared to the ADHD families indicated that, the incidence of the two polymorphisms being transmitted together could be higher in ADHD families.

A Single Nucleotide Polymorphism at DBH, Possibly Associated with Attention-Deficit/Hyperactivity Disorder, Associates with Lower Plasma Dopamine β-Hydroxylase Activity and is in Linkage Disequilibrium with Two Putative Functional Single Nucleotide Polymorphisms

The DBH gene regulates plasma dopamine beta-hydroxylase activity (pDbetaH). Two single nucleotide polymorphisms (SNPs), -1021C-->T (rs1611115; SNP1) and +1603C-->T (rs6271; SNP3), independently influence pDbetaH. Another SNP, commonly known as DBH Taq1A (rs2519152; SNP2) is associated with attention-deficit/hyperactivity disorder (ADHD) in some (but not all) studies. We tested whether 1) SNP2 associates with pDbetaH; and 2) whether linkage disequilibrium (LD) between SNP2 and the other SNPs explains that association. Plasma dopamine beta-hydroxylase activity and genotypes at the SNPs were determined in Caucasian subjects (n = 418). Associations to pDbetaH were examined using analyses of variance (ANOVAs) and LD among the SNPs using estimation maximization. 1) Each polymorphism analyzed alone associated with pDbetaH; 2) SNP2 was in strong LD with SNP1 and SNP3, respectively, but there was no significant LD between SNP1 and SNP3; and 3) analyzed jointly, each SNP contributed significantly and uniquely to plasma DbetaH activity. 1) SNP2 associates with pDbetaH; 2) SNP2 shows LD with SNP1 and SNP3; 3) most of the association between SNP2 and pDbetaH simply reflects that LD; however, 4) SNP2 also appears to exert a small independent effect on pDbetaH, suggesting that SNP2, or another variant in LD with it, uniquely influences pDbetaH.

Haplotype‐controlled analysis of the association of a non‐synonymous single nucleotide polymorphism at DBH (+ 1603C → T) with plasma dopamine β‐hydroxylase activity

The DBH locus controls plasma dopamine beta-hydroxylase activity (pDbetaH). A 5'-upstream single nucleotide polymorphism (SNP) at DBH (-1021C --> T) explains approximately 45% of the variance in pDbetaH, and a non-synonymous SNP in exon 11 (+ 1603C --> T) an additional 2%. However, that regression result underestimates the effect of + 1603C --> T because of its low minor allele frequency. We estimated the biological effect of + 1603C --> T on pDbetaH by comparing subjects of identical -1021CgammaT genotype, in a diagnostically heterogeneous group of subjects of European origin (N = 367). + 1603C --> T genotype associated with pDbetaH within groups of identical genotype at -1021 C --> T, accounting for 5%-16% of the variance. There was no significant linkage disequilibrium between -1021C --> T and + 1603C --> T (D = 0.0058, D' = 0.4774, d(2) = 0.0011, P > 0.05), confirming the validity of assessing the two polymorphisms independently. These results suggest that altered homospecific activity of the enzyme can contribute to variation in pDbetaH. This conclusion informs how associations between DBH and psychiatric disorders should be approached. (c) 2005 Wiley-Liss, Inc.

Association of Dopamine .BETA.-Hydroxylase Polymorphism with Hypertension through Interaction with Fasting Plasma Glucose in Japanese

Dopamine-beta-hydroxylase (DBH) catalyzes the conversion of dopamine to norepinephrine and is released from sympathetic neurons into the circulation. Several lines of evidence, including the finding of elevated plasma DBH activity in essential hypertension, suggest an important role of DBH in hypertension. Recently, a novel polymorphism (-1021C/T) in the 5' flanking region of the DBH gene has been shown to account for 35-52% of the variation in plasma DBH activity. We therefore investigated the possible association between the DBH -1021C/T polymorphism and hypertension in a large Japanese population. Moreover, because the development of hypertension is considered to be due at least partly to gene-environmental interactions, we also investigated the possible interactions between the DBH -1021C/T polymorphism and environmental factors. Consequently, we found a significant interaction between the DBH -1021C/T polymorphism and fasting plasma glucose (FPG) in the association with hypertension. CC homozygotes showed a steeper increase in probability of hypertension with FPG than T allele carriers. We also found a marginally significant trend suggesting the presence of an interaction between the DBH -1021C/T polymorphism and FPG in the association with blood pressure. Consistent with the presence of the interaction, we found that a 19 bp sequence containing the DBH -1021C/T polymorphism includes two palindromic non-canonical E boxes separated by 5 bps, and closely resembles the glucose response element of the L-type pyruvate kinase gene. These findings could be helpful in conducting further molecular and biological studies on the relationship among glucose metabolism, the sympathetic nervous system, and hypertension.

The Structure of Linkage Disequilibrium at the DBH Locus Strongly Influences the Magnitude of Association between Diallelic Markers and Plasma Dopamine β-Hydroxylase Activity

There is currently a great deal of interest in using linkage disequilibrium (LD) mapping to locate both disease and quantitative-trait loci on a genomewide scale. Recent findings suggest that much of the human genome is organized in discrete "blocks" of low haplotype diversity, but the utility of such blocks in identifying genes influencing complex traits is not yet known and must ultimately be tested empirically through use of real data. We recently identified a putative functional polymorphism (-1021C-->T) in the 5' upstream region of the DBH gene that accounted for 35%-52% of the total phenotypic variance in plasma dopamine beta-hydroxylase (DBH) activity in samples from three distinct populations. In the present study, we genotyped 11 diallelic markers at the DBH locus surrounding -1021C-->T in 386 unrelated individuals of European origin. We identified a single 10-kb block containing -1021C-->T, in which four haplotypes comprised 93% of the observed chromosomes. Only markers within the block were highly associated with phenotype (P< or =2.2 x 10(-10)), with one exception. In general, association with phenotype was strongly correlated with the degree of LD between each marker and -1021C-->T. Of four LD measures assessed, d(2) was the best predictor of this relationship. Had one attempted to map quantitative-trait loci for plasma DBH activity on a genomewide basis without prior knowledge of candidate regions and not included (by chance) markers within this haplotype block, the DBH locus might have been missed entirely. These results provide a direct example of the potential value of constructing a haplotype map of the human genome prior to embarking on large-scale association studies.

A haplotype at the DBH locus, associated with low plasma dopamine beta-hydroxylase activity, also associates with cocaine-induced paranoia.

Low levels of dopamine beta-hydroxylase (DbetaH) protein in the plasma or cerebrospinal fluid (CSF) are associated with greater vulnerability to positive psychotic symptoms in several psychiatric disorders. DbetaH level is a stable, genetically controlled trait. DBH, the locus encoding DbetaH protein, is the major quantitative trait locus controlling plasma and CSF DbetaH levels. We therefore hypothesized that DBH variants or haplotypes, associated with low levels of DbetaH in the plasma, would also associate with greater vulnerability to cocaine-induced paranoia. To test this hypothesis, we first showed that a di-allelic variant, DBH*5'-ins/del, located approximately 3 kb 5' to the DBH transcriptional start site, significantly associates with plasma DbetaH activity in European-Americans (n = 66). Linkage disequilibrium analysis of that polymorphism and DBH*444g/a, another di-allelic variant associated with DbetaH levels, demonstrated that alleles of similar association to DbetaH levels are in positive disequilibrium. We then estimated DBH haplotype frequencies in cocaine-dependent European Americans rated for cocaine-induced paranoia (n = 45). As predicted, the low-DbetaH-associated haplotype, Del-a, was significantly more frequent (P = 0.0003) in subjects endorsing cocaine-induced paranoia (n = 29) than in those denying it (n = 16). Comparison to control haplotype frequencies (n = 145 healthy European-Americans) showed that the association predominantly reflected under-representation of Del-a haplotypes in those denying cocaine-induced paranoia. We conclude that: (a) the two DBH polymorphisms we studied are associated with plasma DBH levels; (b) those two polymorphisms are in significant linkage disequilibrium in European Americans, with alleles of similar association to DbetaH levels in positive disequilibrium; and (c) the haplotype associated with low DBH activity is also associated with cocaine-induced paranoia. Molecular Psychiatry (2000) 5, 56-63.

Plasma dopamine beta-hydroxylase activity in psychotic and non-psychotic post-traumatic stress disorder

Recognition and treatment of comorbid chronic psychotic symptoms in post-traumatic stress disorder (PTSD) has become of increasing clinical interest. Altered dopamine beta-hydroxylase (DBH) activity has been reported in mood disorders. Plasma DBH is reduced in major depression with psychosis and elevated in bipolar disorder with psychosis compared with their respective non-psychotic diagnostic groups. DBH is likely a trait marker with interindividual variations secondary to genetic polymorphism. We therefore evaluated DBH activity in PTSD patients with and without psychotic features and compared these groups with age- and gender-matched control subjects. Vietnam combat veterans with PTSD (n=19) (including patients with and without psychotic features) and normal control subjects (n=22) had plasma DBH enzyme activity assayed photometrically. DBH was significantly higher in patients with PTSD with psychotic features than in patients without psychotic features (80.6±13.4 vs. 42.1±7.3 mM/min, P<0.01) and was also higher than normal control subjects (46.12±4.93, P<0.01). Plasma DBH activity may differentiate psychotic and non-psychotic subtypes of PTSD. The observed changes are, interestingly, opposite to those seen in psychotic depression but comparable to psychotic bipolar disorder. Since DBH is a genetic marker, this may reflect individual vulnerabilities to develop psychosis in the context of trauma.

Changes in plasma dopamine-beta-hydroxylase activity during the perioperative period of cardiac surgery: an index of sympathetic nerve activity.

To evaluate the usefulness of plasma dopamine-beta-hydroxylase (DBH) activity as an index of sympathetic nerve activity during cardiac operations, we examined the serial changes in plasma DBH activity, in relation to the plasma noradrenaline (NA) level and hemodynamic parameters, in patients who underwent cardiac surgery. The plasma DBH activity decreased significantly after cardiopulmonary bypass, and remained low during dopamine (DA) infusion until 72 h after the operation. However, recovery of the hemodynamic parameters, being the mean arterial pressure, heart rate and cardiac index, was seen as early as 1-3 h postoperatively. It was therefore assumed that the plasma DBH activity takes a long time to recover after an operation. The time-course changes in the plasma NA level were quite different from the changes in DBH activity, with an apparent negative correlation being observed between them. Thus, there is a possibility that exogenously administered DA, as well as increased plasma NA, might inhibit DBH activity during cardiac surgery. Moreover, since catecholamines are often administered upon completion of cardiac surgery, measurement of the plasma catecholamine level would be inappropriate for evaluating real sympathetic nerve activity. From the results of this study, it is surmised that measurement of the plasma DBH activity could be useful for estimating the intrinsic sympathetic nerve activity of patients who have undergone cardiac surgery.