Polymorphism in exon 6 of the dopamine D2 receptor gene (DRD2) is associated with elevated blood pressure and personality disorders in men

Rosmond, Roland; Rankinen, Tuomo; Chagnon, Monique; Pérusse, Louis; Chagnon, YC; Bouchard, Claude; Björntorp, Per

doi:10.1038/sj.jhh.1001231

Cited by 40 publications

(21 citation statements)

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“…12,30,31 Interestingly, this polymorphism has been reported to have an endocrine correlate. 32 In fact, a recent study carried out on a cohort of subjects from the Sweden National Population Registry reported a high prevalence of 957T genotype in subjects with high systolic and diastolic blood pressure. On the basis of this association, the authors suggested that this variant might cause defective dopamine signaling, resulting in elevated blood pressure due to deficient inhibition of noradrenaline release from sympathetic nerve endings and aldosterone secretion from the adrenals.…”

Section: Filopanti Et Almentioning

confidence: 99%

“…On the basis of this association, the authors suggested that this variant might cause defective dopamine signaling, resulting in elevated blood pressure due to deficient inhibition of noradrenaline release from sympathetic nerve endings and aldosterone secretion from the adrenals. 32 Indeed, increasing in vitro and in vivo evidence indicates that this change in DRD2, though synonymous, has marked functional consequences. In particular, it has been demonstrated that 957T, rather than being silent, altered the predicted mRNA folding, leading to a decrease in mRNA stability and translation.…”

Section: Filopanti Et Almentioning

confidence: 99%

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Dopamine D2 receptor gene polymorphisms and response to cabergoline therapy in patients with prolactin-secreting pituitary adenomas

et al. 2008

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Dopamine-agonist cabergoline (CB) reduces prolactin (PRL) secretion and tumor size in 80% of patients with prolactin-secreting adenomas (PRL-omas) by binding type 2 dopamine receptor (DRD2). The mechanisms responsible for resistance to CB remain largely unknown. To assess the association of DRD2 with sensitivity to CB, TaqI-A1/A2, TaqI-B1/B2, HphI-G/T and NcoI-C/T genotypes were determined in a cross-sectional retrospective study, including 203 patients with PRL-oma. DRD2 alleles frequencies did not differ between patients and 212 healthy subjects. Conversely, NcoI-T allele frequency was higher in resistant rather than responsive patients, considering both PRL normalization (56.6 vs 45.3%, P ¼ 0.038) and tumor shrinkage (70.4 vs 41.4%, P ¼ 0.006). Finally, [TaqI A1À/TaqI B1À/HphI TÀ/NcoI TÀ] haplotype was found in 34.5% of patients normalizing PRL with p3 mg/ week of CB vs 11.3% of resistants (P ¼ 0.021). In conclusion, resistance to CB was associated with DRD2 NcoI-T þ allele, consistent with evidence suggesting that this variant may lead to reduction and instability of DRD2 mRNA or protein.

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Section: Filopanti Et Almentioning

confidence: 99%

Section: Filopanti Et Almentioning

confidence: 99%

Dopamine D2 receptor gene polymorphisms and response to cabergoline therapy in patients with prolactin-secreting pituitary adenomas

et al. 2008

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“…1,2 Loci in chromosome 11, where the D 2 R gene is located, are linked to hypertension. 5,6 A polymorphism in exon 6 of the D 2 R gene is associated with elevated blood pressure, 7 and a TaqI polymorphism is associated with human essential hypertension. 8 Several D 2 R polymorphisms are associated with decreased D 2 R expression 9,10 and affect D 2 R mRNA stability and synthesis of the receptor.…”

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confidence: 99%

Reactive Oxygen Species–Dependent Hypertension in Dopamine D ₂ Receptor–Deficient Mice

et al. 2007

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Abstract-Dysfunction of D 2 -like receptors has been reported in essential hypertension. Disruption of D 2 R in mice (D 2 Ϫ/Ϫ ) results in high blood pressure, and several D 2 R polymorphisms are associated with decreased D 2 R expression. Because D 2 R agonists have antioxidant activity, we hypothesized that increased blood pressure in D 2 Ϫ/Ϫ is related to increased oxidative stress. D 2 Ϫ/Ϫ mice had increased urinary excretion of 8-isoprostane, a parameter of oxidative stress; increased activity of reduced nicotinamide-adenine dinucleotide phosphate oxidase in renal cortex; increased expression of the reduced nicotinamide-adenine dinucleotide phosphate oxidase subunits Nox1, Nox2, and Nox4; and decreased expression of the antioxidant enzyme heme-oxygenase-2 in the kidneys, suggesting that regulation of reactive oxygen species (ROS) production by D 2 R involves both pro-oxidant and antioxidant systems. Apocynin, a reduced nicotinamide-adenine dinucleotide phosphate oxidase inhibitor, or hemin, an inducer of heme oxigenase-1, normalized the blood pressure in D 2 Ϫ/Ϫ mice. Because D 2 Rs in the adrenal gland are implicated in aldosterone regulation, we evaluated whether alterations in aldosterone secretion contribute to ROS production in this model. Urinary aldosterone was increased in D 2 Ϫ/Ϫ mice and its response to a high-sodium diet was impaired. Spirolactone normalized the blood pressure in D 2 Ϫ/Ϫ mice and the renal expression of Nox1 and Nox4, indicating that the increased blood pressure and ROS production are, in part, mediated by impaired aldosterone regulation. However, spironolactone did not normalize the excretion of 8-isoprostane and had no effect on expression of Nox2 or heme-oxygenase-2. Our results show that the D 2 R is involved in the regulation of ROS production and that, by direct and indirect mechanisms, altered D 2 R function may result in ROS-dependent hypertension. [1][2][3] There is abundant evidence that an intact dopaminergic system is necessary to maintain normal blood pressure and that genetic hypertension is associated with alterations in dopamine production and receptor function. [1][2][3][4] In humans and rodents, some dopamine receptor genes and their regulators are in loci linked to hypertension. 3,5 The natriuretic effect of D 1 -like agonists is impaired in genetically hypertensive rats 3,4 and in human essential hypertension. 3,4 Alterations in D 2 -like receptor function have also been reported in hypertension. 1,2 Loci in chromosome 11, where the D 2 R gene is located, are linked to hypertension. 5,6 A polymorphism in exon 6 of the D 2 R gene is associated with elevated blood pressure, 7 and a TaqI polymorphism is associated with human essential hypertension. 8 Several D 2 R polymorphisms are associated with decreased D 2 R expression 9,10 and affect D 2 R mRNA stability and synthesis of the receptor. 11 The disruption of any of the dopamine receptor genes in mice produces dopamine receptor subtype-specific hypertension. 3,[12][13][14] Specifically, disruption of the D 2 R...

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“…DRD2 polymorphisms have previously been linked to schizoid/avoidant behavior [70] and, correspondingly, cluster A (paranoid, schizotypal, schizoid) PDs [71]. Most recently, Jonsson et al [72] genotyped 235 healthy subjects in whom an association was detected between the -141C ins/del variant of the DRD2 and personality detachment, the latter of which negatively correlates with the NEO-PI-R extraversion and agreeableness scale and TCI RD.…”

Section: Detachmentmentioning

confidence: 96%

Molecular genetics of personality

Noblett

Coccaro

2005

Curr Psychiatry Rep

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Although initial reports of genetic contributions to personality dimensions were promising, continued empirical support remains controversial. The focus has largely revolved around polymorphisms of the serotonin transporter gene-linked polymorphic region and the D4 dopamine receptor subtype. Equivocal findings likely stem from numerous sources including ethnic diversity of subject samples, phenotypic characterization of personality traits, and insufficient sample sizes. Research has begun to shy away from single gene causation in support of more complex polygenic models of personality traits. This search has identified numerous other candidate genes including dopamine D2 and D3 receptor subtypes, serotonin receptors, and catecholaminergic enzymes, to name a few. This article endeavors to review and evaluate the most recent literature within the context of this burgeoning field. Some considerations for future research are presented in summary.

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Polymorphism in exon 6 of the dopamine D2 receptor gene (DRD2) is associated with elevated blood pressure and personality disorders in men

Cited by 40 publications

References 27 publications

Dopamine D2 receptor gene polymorphisms and response to cabergoline therapy in patients with prolactin-secreting pituitary adenomas

Dopamine D2 receptor gene polymorphisms and response to cabergoline therapy in patients with prolactin-secreting pituitary adenomas

Reactive Oxygen Species–Dependent Hypertension in Dopamine D ₂ Receptor–Deficient Mice

Molecular genetics of personality

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Polymorphism in exon 6 of the dopamine D2 receptor gene (DRD2) is associated with elevated blood pressure and personality disorders in men

Cited by 40 publications

References 27 publications

Dopamine D2 receptor gene polymorphisms and response to cabergoline therapy in patients with prolactin-secreting pituitary adenomas

Dopamine D2 receptor gene polymorphisms and response to cabergoline therapy in patients with prolactin-secreting pituitary adenomas

Reactive Oxygen Species–Dependent Hypertension in Dopamine D 2 Receptor–Deficient Mice

Molecular genetics of personality

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Product

Resources

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Reactive Oxygen Species–Dependent Hypertension in Dopamine D ₂ Receptor–Deficient Mice