Common variants in P2RY11 are associated with narcolepsy

Center for Sleep Sciences and Department of Psychiatry, Stanford University School of Medicine, Palo Alto, California, USA.
Nature Genetics (Impact Factor: 29.35). 01/2011; 43(1):66-71. DOI: 10.1038/ng.734
Source: PubMed

ABSTRACT Growing evidence supports the hypothesis that narcolepsy with cataplexy is an autoimmune disease. We here report genome-wide association analyses for narcolepsy with replication and fine mapping across three ethnic groups (3,406 individuals of European ancestry, 2,414 Asians and 302 African Americans). We identify a SNP in the 3' untranslated region of P2RY11, the purinergic receptor subtype P2Y₁₁ gene, which is associated with narcolepsy (rs2305795, combined P = 6.1 × 10⁻¹⁰, odds ratio = 1.28, 95% CI 1.19-1.39, n = 5689). The disease-associated allele is correlated with reduced expression of P2RY11 in CD8(+) T lymphocytes (339% reduced, P = 0.003) and natural killer (NK) cells (P = 0.031), but not in other peripheral blood mononuclear cell types. The low expression variant is also associated with reduced P2RY11-mediated resistance to ATP-induced cell death in T lymphocytes (P = 0.0007) and natural killer cells (P = 0.001). These results identify P2RY11 as an important regulator of immune-cell survival, with possible implications in narcolepsy and other autoimmune diseases.

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Available from: Lawrence Steinman, Sep 26, 2015
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    • "The generation of human hypothalamic neurons from diseasecarrying iPSCs would enable diseases of hypothalamic origin to be studied (supplementary material Table S1). For example, narcolepsy is associated with both genetic and environmental factors, but the causes of HCRT neuron loss are not well understood (Chabas et al., 2003; Kornum et al., 2010; Mignot, 1998; Winkelmann et al., 2012). Although in vitro systems might be insufficient to recapitulate the complex interactions that likely precipitate an autoimmune attack, they might enable cell-autonomous mechanisms of HCRT neuron loss in narcolepsy to be tested in HCRT neurons generated from the iPS cells of individuals with narcolepsy. "
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    ABSTRACT: Hypothalamic neurons orchestrate many essential physiological and behavioral processes via secreted neuropeptides, and are relevant to human diseases such as obesity, narcolepsy and infertility. We report the differentiation of human pluripotent stem cells into many of the major types of neuropeptidergic hypothalamic neurons, including those producing pro-opiolemelanocortin, agouti-related peptide, hypocretin/orexin, melanin-concentrating hormone, oxytocin, arginine vasopressin, corticotropin-releasing hormone (CRH) or thyrotropin-releasing hormone. Hypothalamic neurons can be generated using a 'self-patterning' strategy that yields a broad array of cell types, or via a more reproducible directed differentiation approach. Stem cell-derived human hypothalamic neurons share characteristic morphological properties and gene expression patterns with their counterparts in vivo, and are able to integrate into the mouse brain. These neurons could form the basis of cellular models, chemical screens or cellular therapies to study and treat common human diseases. © 2015. Published by The Company of Biologists Ltd.
    Development 02/2015; 142(4):633-43. DOI:10.1242/dev.117978 · 6.46 Impact Factor
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    • "The pathogenesis of sporadic narcolepsy with cataplexy is likely autoimmune with hypocretin neurons being a target (Kornum et al., 2011a), and possibly interacting with other neurotransmission systems during development (Sundvik et al., 2011). Narcolepsy with cataplexy is strongly associated with HLA– DQB1*06:02 (Mignot et al., 1994), an effect also modulated by the presence of other HLA subtypes (Mignot et al., 2001; Hor et al., 2010), and by polymorphisms in the T cell receptor alpha (Hallmayer et al., 2009; Hor et al., 2010), P2YR11 receptor and other loci (Kornum et al., 2011b; Faraco et al., 2013). Clinical and biochemical evidence temporally links the onset of narcolepsy with cataplexy symptoms with an activation of the immune system by infection, either bacterial such as streptococcal (Aran et al., 2009), or viral such as H1N1 flu or vaccination (Han et al., 2011; Partinen et al., 2012), or with an autoimmune response proved by production of self-targeted antibodies (Cvetkovic-Lopes et al., 2010; Kawashima et al., 2010). "
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    ABSTRACT: Our aim was to investigate the natural evolution of cataplexy and polysomnographic features in untreated children with narcolepsy with cataplexy. To this end, clinical, polysomnographic, and cataplexy-video assessments were performed at diagnosis (mean age of 10 ± 3 and disease duration of 1 ± 1 years) and after a median follow-up of 3 years from symptom onset (mean age of 12 ± 4 years) in 21 children with narcolepsy with cataplexy and hypocretin 1 deficiency (tested in 19 subjects). Video assessment was also performed in two control groups matched for age and sex at first evaluation and follow-up and was blindly scored for presence of hypotonic (negative) and active movements. Patients' data at diagnosis and at follow-up were contrasted, compared with controls, and related with age and disease duration. At diagnosis children with narcolepsy with cataplexy showed an increase of sleep time during the 24 h; at follow-up sleep time and nocturnal sleep latency shortened, in the absence of other polysomnographic or clinical (including body mass index) changes. Hypotonic phenomena and selected facial movements decreased over time and, tested against disease duration and age, appeared as age-dependent. At onset, childhood narcolepsy with cataplexy is characterized by an abrupt increase of total sleep over the 24 h, generalized hypotonia and motor overactivity. With time, the picture of cataplexy evolves into classic presentation (i.e. brief muscle weakness episodes triggered by emotions), whereas total sleep time across the 24 h decreases, returning to more age-appropriate levels.
    Brain 10/2013; 136(12). DOI:10.1093/brain/awt277 · 9.20 Impact Factor
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    • "For example, sleep disorders such as sleep apnea (Svanborg and Guilleminault, 1996), narcolepsy (van den Hoed et al., 1981), and restless legs syndrome (Montplaisir et al., 1998), generally do not result in reductions in total sleep time. These medical conditions are characterized by inflammation (Kornum et al., 2011; Shamsuzzaman et al., 2003; Weinstock et al., 2012), which may be induced by sleep fragmentation per se (Bryant et al., 2004; Krueger et al., 2001; Mullington et al., 2009; Opp and Toth, 2003). Additionally, shift work (Akerstedt, 1998), caregiving (Happe and Berger, 2002; McCurry et al., 2007) or the care of a newborn (Hunter et al., 2009) disrupt sleep but rarely result in total sleep deprivation. "
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    ABSTRACT: Sleep disruption is a frequent occurrence in modern society. Whereas many studies have focused on the consequences of total sleep deprivation, few have investigated the condition of sleep disruption. We disrupted sleep of mice during the light period for 9 consecutive days using an intermittently-rotating disc. Electroencephalogram (EEG) data demonstrated that non-rapid eye movement (NREM) sleep was severely fragmented and REM sleep was essentially abolished during the 12h light period. During the dark period, when sleep was not disrupted, neither NREM sleep nor REM sleep times differed from control values. Analysis of the EEG revealed a trend for increased power in the peak frequency of the NREM EEG spectra during the dark period. The fragmentation protocol was not overly stressful as body weights and water consumption remained unchanged, and plasma corticosterone did not differ between mice subjected to 3 or 9 days of sleep disruption and home cage controls. However, mice subjected to 9 days of sleep disruption by this method responded to lipopolysaccharide with an exacerbated febrile response. Existing methods to disrupt sleep of laboratory rodents often subject the animal to excessive locomotion, vibration, or sudden movements. This method does not suffer from any of these confounds. This study demonstrates that prolonged sleep disruption of mice exacerbates febrile responses to lipopolysaccharide. This device provides a method to determine mechanisms by which chronic insufficient sleep contributes to the etiology of many pathologies, particularly those with an inflammatory component.
    Journal of Neuroscience Methods 07/2013; 219(1). DOI:10.1016/j.jneumeth.2013.07.008 · 2.05 Impact Factor
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