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 / 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.. - In: NATURE GENETICS. - ISSN 1061-4036. - 43:1(2011), pp. 66-71. [10.1038/ng.734]
Common variants in P2RY11 are associated with narcolepsy
Plazzi G.;Poli F.;
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.
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