P2RX7: Expression Responds to Sleep Deprivation and Associates with Rapid Cycling in Bipolar Disorder Type 1

Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
PLoS ONE (Impact Factor: 3.23). 08/2012; 7(8):e43057. DOI: 10.1371/journal.pone.0043057
Source: PubMed


Rapid cycling is a severe form of bipolar disorder with an increased rate of episodes that is particularly treatment-responsive to chronotherapy and stable sleep-wake cycles. We hypothesized that the P2RX7 gene would be affected by sleep deprivation and be implicated in rapid cycling.
To assess whether P2RX7 expression is affected by total sleep deprivation and if variation in P2RX7 is associated with rapid cycling in bipolar patients.
Gene expression analysis in peripheral blood mononuclear cells (PBMCs) from healthy volunteers and case-case and case-control SNP/haplotype association analyses in patients.
Healthy volunteers at the sleep research center, University of California, Irvine Medical Center (UCIMC), USA (n = 8) and Swedish outpatients recruited from specialized psychiatric clinics for bipolar disorder, diagnosed with bipolar disorder type 1 (n = 569; rapid cycling: n = 121) and anonymous blood donor controls (n = 1,044).
P2RX7 RNA levels were significantly increased during sleep deprivation in PBMCs from healthy volunteers (p = 2.3*10(-9)). The P2RX7 rs2230912 _A allele was more common (OR = 2.2, p = 0.002) and the ACGTTT haplotype in P2RX7 (rs1718119 to rs1621388) containing the protective rs2230912_G allele (OR = 0.45-0.49, p = 0.003-0.005) was less common, among rapid cycling cases compared to non-rapid cycling bipolar patients and blood donor controls.
Sleep deprivation increased P2RX7 expression in healthy persons and the putatively low-activity P2RX7 rs2230912 allele A variant was associated with rapid cycling in bipolar disorder. This supports earlier findings of P2RX7 associations to affective disorder and is in agreement with that particularly rapid cycling patients have a more vulnerable diurnal system.

    • "According to Backlund and co-authors P2X7 receptor gene expression is associated with bipolar disorders, especially in the form of a rapid cycling (rapid cycling bipolar disorder , RCBD), when 4 or more periods of depression or mania occur in a year (Backlund et al., 2012). These authors have found that sleep deprivation causes an increase in receptor gene expression in healthy subjects, and that in type 1 of bipolar disorders functional polymorphism of P2X7 receptor gene accompanies the occurence of the rapid cycling form (Backlund et al., 2012). Furthermore, expression of this receptor is associated not only with depression, but also with anxiety disorders and cognitive symptoms observed in mania (Erhardt et al., 2007; Hejjas et al., 2009; Backlund et al., 2011; Backlund et al., 2012). "
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    ABSTRACT: Ecto-purines and ecto-pyrimidines are present in the extracellular space of the central nervous system (CNS). Together with P1 and P2 receptors and nucleotides metabolizing ecto-enzymes, they make signaling system involved in neurotransmission, the modulation of sensory signals, including pain stimuli conduction, and the induction of apoptosis and necrosis of the cells. Purines and pyrimidines have a dual effect: positive (neuroprotective) of nucleosides, and negative (pro-inflammatory and pro-apoptotic) of nucleotides. Adenosine-5'-triphosphate (ATP) in the CNS triggers the pro-inflammatory reactions, predominantly by activation of the P2X7 receptor, which results in production and release of pro-inflammatory cytokines. In contrast to ATP, adenosine acts generally as an anti-inflammatory agent and plays an important role in neuroprotection. Currently, it is believed that the initiation of CNS diseases, including mental disorders, is caused by any imbalance between the concentration of ATP and adenosine in the extracellular space. Genetic tests provide also the evidence for the participation of purinergic signaling in psychiatric disorders. It is believed that any action leading to the effective increase of adenosine concentration: activation of nucleotide metabolizing ecto-enzymes (mainly NTPDases - nucleoside triphosphate diphosphohydrolases), inhibition of adenosine deaminase and/or adenosine kinase activity as well as therapies using P1 receptor agonists (adenosine or its analogues) might be beneficial in therapy of psychiatric disorders.
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    • "The P2X7R, a member of the P2X subfamily of purinergic receptors, is a cation-selective ion channel activated by extracellular ATP. When overactivated , P2XR undergoes a channel-to-pore transition that causes the opening of a non-selective plasma membrane pore permeable to aqueous solutes up to a MW of 900 D. The precise physiological function of P2X7R is as yet unknown, but rather intriguingly this gene is highly polymorphic, with over thirty single-nucleotide polymorphisms (SNPs) described (Backlund et al., 2012; gene=P2RX7&search=97e20c4c94f763ef865b40c278da3b2d). "
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    ABSTRACT: Inflammation is a key factor in the onset and progression of Alzheimer's disease (AD). The P2X7 receptor (P2X7R) is increasingly recognized as key pro-inflammatory receptor. A recent study has shown that activation of microglia by amyloid β (Aβ) and associated release of IL-1β, requires P2X7R expression. In this study we assessed by RT-PCR in genomic DNA samples, the frequency of two single-nucleotide polymorphisms (SNP) of P2X7R in AD patients compared to age-matched non demented elderly. Our data show that the 489C>T SNP was significantly less frequent in AD patients than in controls (p = 0.01), whereas there was no statistical difference in 1513A>C frequency in either groups. In addition, presence of the 1513C allele and absence of the 489C allele decreased the probability of having AD by about four fold. In conclusion, our data show a strong negative association between the P2X7R 489C>T polymorphism and AD, especially in the presence of the 1513C allele.
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    • "There were 581 studies relevant to the searching terms (Pubmed: 54; Embase: 59; Elsevier Science Direct: 424; Cochrane Library: 0; CBM: 44). Totally, 12 studies examined the association between P2RX7 gene polymorphisms and mood disorders [16]–[25], [33], [34]. Of these, 2 studies were excluded (1 was excluded due to duplicate report; 1 was excluded due to not rs2230912 polymorphism) [33], [34]. "
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    ABSTRACT: To assess the association of P2RX7 gene rs2230912 polymorphism with mood disorders using a meta-analysis. DATA WERE COLLECTED FROM THE FOLLOWING ELECTRONIC DATABASES: PubMed, Excerpta Medica Database, Elsevier Science Direct, Cochrane Library, and Chinese Biomedical Literature Database, with the last report up to April 1, 2013. Odds ratio (OR) with 95% confidence interval (CI) was used to assess the strength of the association. Dependent on the results of heterogeneity test among individual studies, the fixed effect model (Mantel-Haenszel) or random effect model (DerSimonian-Laird) was selected to summarize the pooled OR. We identified 13 separate studies using search (6,962 cases and 9,262 controls). We detected significant between-study heterogeneity. No significant association of this polymorphism with mood disorders was found (P>0.05). We also performed disease-specific meta-analysis in unipolar depression and bipolar disorder. No significant association of this polymorphism with unipolar depression or bipolar disorder was found (P>0.05). Additionally, we performed subgroup analysis by different types of cases. No significant association of this polymorphism with mood disorders in clinical cohorts or population-based cohorts (P>0.05). A significant association of this polymorphism with mood disorders was found for the allele contrast in family-based cohorts (OR = 1.26, 95%CI = 1.05-1.50, P = 0.01). Overall, our meta-analysis suggests that P2RX7 gene rs2230912 polymorphism may not contribute to the risk of developing mood disorders using a case-control design. Given the discordance in the subgroup analysis by different types of cases, further studies based on larger sample size are still needed.
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