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

Mustapić, Maja; Pivac, Nela; Kozarić‐Kovačić, Dragica; Deželjin, Martina; Cubells, Joseph F.; Mück‐Šeler, Dorotea

doi:10.1002/ajmg.b.30526

Cited by 60 publications

(53 citation statements)

References 19 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…11, 14–16 The profound effect of these SNPs on circulating DBH levels is supported by their large effect on mRNA expression in liver and lung. We extrapolate from these results that genetic effects likely occur in all sympathetically innervated organs and thereby affect serum DBH.…”

Section: Discussionmentioning

confidence: 99%

“…Significant inter-individual variability in plasma DBH levels has been associated with genetic DBH variants. The minor allele ( T ) of the promoter single nucleotide polymorphism (SNP) rs1611115 (−1021C/T) is associated with lower serum DBH levels, accounting for 35–52% of the variation across populations, 11, 14–16 while individuals homozygous for the C allele have increased plasma norepinephrine levels. 19 However, it remains unknown how rs1611115- T reduces circulating DBH and norepinephrine levels.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Regulatory Polymorphisms in Human DBH Affect Peripheral Gene Expression and Sympathetic Activity

Barrie

Verma

Pendergrass

et al. 2014

Circulation Research

Self Cite

View full text Add to dashboard Cite

Rationale Dopamine β-hydroxylase (DBH) catalyzes the conversion of dopamine to norepinephrine in the CNS and peripherally. DBH variants are associated with large changes in circulating DBH and implicated in multiple disorders; yet causal relationships and tissue-specific effects remain unresolved. Objective To characterize regulatory variants in DBH, effect on mRNA expression, and role in modulating sympathetic tone and disease risk. Methods and Results Analysis of DBH mRNA in human tissues confirmed high expression in the locus coeruleus (LC) and adrenal gland, but also in sympathetically innervated organs (liver>lung>heart). Allele-specific mRNA assays revealed pronounced allelic expression differences in the liver (2–11-fold) attributable to promoter rs1611115 and exon 2 rs1108580, but only small differences in LC and adrenals. These alleles were also associated with significantly reduced mRNA expression in liver and lung. Although DBH protein is expressed in other sympathetically innervated organs, mRNA levels were too low for analysis. In mice, hepatic Dbh mRNA levels correlated with cardiovascular risk phenotypes. The minor alleles of rs1611115 and rs1108580 were associated with sympathetic phenotypes including angina pectoris. Testing combined effects of these variants suggested protection against myocardial infarction in three separate clinical cohorts. Conclusions We demonstrate profound effects of DBH variants on expression in two sympathetically innervated organs, liver and lung, but not in adrenals and brain. Preliminary results demonstrate an association of these variants with clinical phenotypes responsive to peripheral sympathetic tone. We hypothesize that in addition to endocrine effects via circulating DBH and norepinephrine, the variants act in sympathetically innervated target organs.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Regulatory Polymorphisms in Human DBH Affect Peripheral Gene Expression and Sympathetic Activity

Barrie

Verma

Pendergrass

et al. 2014

Circulation Research

Self Cite

View full text Add to dashboard Cite

show abstract

“…Lower plasma DBH activity has been reported in different psychopathological disorders [59]. Although evidence suggests a hyperactive SAM system in patients with PTSD [60,61,62,63], Mustapic et al [64] reported lower DBH activity in war veterans with PTSD compared to war veterans without PTSD, indicating that those who exhibited lower plasma DBH activity after a traumatic event were less resilient and more vulnerable to developing PTSD. This finding is consistent with the decrease in catecholamine levels observed on day 24 in the passive subjects.…”

Section: Discussionmentioning

confidence: 99%

Coping with Chronic Social Stress in Mice: Hypothalamic-Pituitary-Adrenal/ Sympathetic-Adrenal-Medullary Axis Activity, Behavioral Changes and Effects of Antalarmin Treatment: Implications for the Study of Stress-Related Psychopathologies

Pérez-Tejada¹,

Arregi²,

Gómez-Lázaro³

et al. 2013

Neuroendocrinology

View full text Add to dashboard Cite

The aim of this study was to analyze the individual differences that lead to the development of psychopathological changes in response to chronic social stress. We also assessed the ability of an antagonist of the corticotrophin-releasing hormone (CRH) receptors to reverse the effects of stress. Male adult mice were exposed to repeated defeat experiences for 21 days using a sensorial contact model. After 18 days of defeat, two groups of subjects were established (active and passive), according to their behaviors during social confrontation. Antalarmin treatment was given for 4 and 6 days. The results corroborated previous data indicating that subjects who adopted a passive coping strategy had higher corticosterone levels after 21 days of defeat and decreased resting levels 3 days later. Moreover, they showed higher resting expression levels of hypothalamic CRH than their active counterparts. On day 24, the experimental animals were subjected to another social defeat to determine whether the stress response remained. The increase in corticosterone and hypothalamic CRH levels was similar for all of the stressed subjects, but the passive subjects also had a greater CRH response in the amygdala. Passive subjects had decreased levels of adrenal dopamine β-hydroxylase, tyrosine hydroxylase and plasma adrenaline compared to the active subjects, and lower plasma noradrenaline levels than manipulated controls. The passive profile of physiological changes in both the hypothalamic-pituitary-adrenal and sympathetic-adrenal-medullary (SAM) axes has been associated with changes related to mood disorders, such as posttraumatic stress disorder and depression. The active coping profile is characterized by similar corticosterone resting levels to controls and increased SAM activity. Both profiles showed alterations in the novel palatable and forced swimming tests, with the passive profile being the most vulnerable to the effects of stress in this last test. Pharmacological treatment with antalarmin failed to reverse the effects of stress.

show abstract

“…This reasoning has led to several studies examining gene variants in the CRH gene [18], the glucocorticoid receptor (GR) gene [19], and in FKBP5 [20,21], a gene which regulates cortisol-binding affinity and nuclear translocation of GRs. Because the dopaminergic and adrenergic systems are also implicated in stress and fear biology, variation in dopamine regulating genes (e.g., dopamine β-hydroxylase, dopamine transporter and DRD2 genes) has been investigated in association with PTSD [22][23][24][25][26][27][28]. Variation in the serotonin transporter gene has been widely studied in association with PTSD [29][30][31] and in particular in the context of gene by environment studies [32][33][34] (see below for further discussion of this type of design).…”

Section: Gene Association Studies In Ptsdmentioning

confidence: 99%

The Role of Genes in Defining a Molecular Biology of PTSD

Yehuda

Koenen²,

Galea

et al. 2011

Disease Markers

View full text Add to dashboard Cite

Abstract. Because environmental exposure to trauma is the sine qua non for the development of Post Traumatic Stress Disorder (PTSD), the recent focus on genetic studies has been noteworthy. The main catalyst for such studies is the observation from epidemiological studies that not all trauma survivors develop this disorder. Furthermore, neuroendocrine findings suggest preexisting hormonal alterations that confer risk for PTSD. This paper presents the rationale for examining genetic factors in PTSD and trauma exposure, but suggests that studies of genotype may only present a limited picture of the molecular biology of this disorder. We describe the type of information that can be obtained from candidate gene and genomic studies that incorporate environmental factors in the design (i.e., gene -environment interaction and gene-environment correlation studies) and studies that capitalize on the idea that environment modifies gene expression, via epigenetic or other molecular mechanisms. The examination of epigenetic mechanisms in tandem with gene expression will help refine models that explain how PTSD risk, pathophysiology, and recovery is mediated by the environment. Since inherited genetic variation may also influence the extent of epigenetic or gene expression changes resulting from the environment, such studies should optimally be followed up by studies of genotype. If PTSD is a condition precipitated by environmental exposure, why examine genes?For at least two decades after the diagnosis of PTSD was established in 1980, it would have been unheard of to propose that genes might be involved in the etiology or pathogenesis of this condition. PTSD was initially defined as a disorder that resulted from exposure to a traumatic environmental event. The diagnosis was designed to describe universal effects of extreme stress that linger even after the stressor is removed. The theoretical contribution that this made to the biopsychosocial model of mental illness was the realization that the effects of an environmental event are not limited to initial exposure to the event, but can also persist for years and even decades. These long-term effects were conceptualized as being a function of the intensi- * Corresponding author. E-mail: Rachel.Yehuda@va.gov. ty and severity of the event that precipitated the initial symptoms.The implication of the PTSD diagnosis was that the adverse effects of exposure to chronic stressors (e.g., illness, family conflict, or financial pressures) could be alleviated or even eliminated if the challenge to the person was removed (and hence were not precipitants of PTSD). In contrast, the effects of exposure to lifethreatening events like interpersonal violence, combat, and accidents that caused intense fear, helplessness and horror were not only persistent, but were of a specific and universal nature. The basic phenomenology of PTSD asserted that following trauma exposure, the survivor experiences unwanted, uncontrollable memories of the event that generate physical and emotional responses resem...

show abstract

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

Cited by 60 publications

References 19 publications

Regulatory Polymorphisms in Human DBH Affect Peripheral Gene Expression and Sympathetic Activity

Regulatory Polymorphisms in Human DBH Affect Peripheral Gene Expression and Sympathetic Activity

Coping with Chronic Social Stress in Mice: Hypothalamic-Pituitary-Adrenal/ Sympathetic-Adrenal-Medullary Axis Activity, Behavioral Changes and Effects of Antalarmin Treatment: Implications for the Study of Stress-Related Psychopathologies

The Role of Genes in Defining a Molecular Biology of PTSD

Contact Info

Product

Resources

About