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.

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Available from: Pernilla Nikamo, Oct 09, 2015
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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.
    Experimental Gerontology 12/2014; 60. DOI:10.1016/j.exger.2014.10.009 · 3.49 Impact Factor
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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.
    PLoS ONE 02/2014; 9(2):e88575. DOI:10.1371/journal.pone.0088575 · 3.23 Impact Factor
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    • "For example, P2RX7 knock out mice show an antidepressant-like phenotype and also a more pronounced response to a subefficacious dose of imipramine (Skaper et al., 2010; Burnstock et al., 2011). In addition, recent results indicated that sleep deprivation (as a treatment modality for mood disorders) alter the expression level of P2X7 receptors in peripheral blood cells (Backlund et al., 2012). Taking into consideration that inflammatory cytokines are suggested to play a role in the molecular pathogenesis of depression (for instance, central administration of TNF-a evokes a behavioral state in animals which highly resembles to depression in humans) and also that P2X7 receptors are involved in the regulation of cytokine release in the central nervous system (e.g., release of TNF-a from microglia cells) we may assume that inflammatory cytokines may mediate the association between genetic variants of P2RX7 and altered risks for mood disorders (Bennett, 2007; Skaper et al., 2010; Soronen et al., 2011). "
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    ABSTRACT: BACKGROUND: Major depressive disorder (MDD) and bipolar disorder (BPD) have significant genetic predisposition. The P2RX7 gene (coding for P2X7 purinergic receptor) has been suggested as a susceptibility gene for both MDD and BPD. In the current study the genetic effects of rs2230912 (Gln460Arg) and rs1653625 (located in the 3' untranslated region of the P2RX7 gene) were explored in mood disorders. METHODS: Genotype frequencies were established in 315 patients (195 with MDD and 120 with BPD diagnosis) and in 373 controls. Depression severity was assessed by the clinician-rated Montgomery-Åsberg Depression Rating Scale (MADRS) and by the self-report Hospital Anxiety and Depression Scale (HADS). RESULTS: In the case-control analysis we did not find any significant differences between genotype frequencies of either BPD or MDD cases and controls. However, BPD patients carrying at least one rs2230912G-allele scored higher on both MADRS and HADS-depression scale (nominal p-value was 0.028 and 0.003, respectively). The rs1653625AA genotype was also associated with higher depression scores in the BPD group (nominal p-value of MADRS: 0.019, HADS-depression: 0.017). After correction for multiple testing, the association between rs2230912 and HADS-depression score remained significant in the BPD group (p<0.006); this genetic effect explained 9% of the variance (partial η(2)=0.09). In the MDD group we did not find any significant genetic effect. LIMITATIONS: The relatively small number of BPD patients warrants for a replication study. CONCLUSIONS: Our genetic association study supports the association between P2RX7 gene and severity of depressive symptoms in BPD patients.
    Journal of Affective Disorders 04/2013; 150(1). DOI:10.1016/j.jad.2013.02.033 · 3.38 Impact Factor
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