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.

Common variants in P2RY11 are associated with narcolepsy

PLAZZI, GIUSEPPE;POLI, FRANCESCA;PIZZA, FABIO;
2011

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.
Kornum B.R.; Kawashima M.; Faraco J.; Lin L.; Rico T.J.; Hesselson S.; Axtell R.C.; Kuipers H.; Weiner K.; Hamacher A.; Kassack M.U.; Han F.; Knudsen S.; Li J.; Dong X.; Winkelmann J.; Plazzi G.; Nevsimalova S.; Hong S.C.; Honda Y.; Honda M.; Hogl B.; Ton T.G.; Montplaisir J.; Bourgin P.; Kemlink D.; Huang Y.S.; Warby S.; Einen M.; Eshragh J.L.; Miyagawa T.; Desautels A.; Ruppert E.; Hesla P.E.; Poli F.; Pizza F.; Frauscher B.; Jeong J.H.; Lee S.P.; Strohl K.P.; Longstreth W.T. Jr.; Kvale M.; Dobrovolna M.; Ohayon M.M.; Nepom G.T.; Wichmann H.E.; Rouleau G.A.; Gieger C.; Levinson D.F.; Gejman P.V.; Meitinger T.; Peppard P.; Young T.; Jennum P.; Steinman L.; Tokunaga K.; Kwok P.Y.; Risch N.; Hallmayer J.; Mognot E.
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11585/97185
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