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). 10/2011; 43(1):66-71. DOI: 10.1038/ng.734
Source: PubMed


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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    • "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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    • "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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