Common variants in P2RY11 are associated with narcolepsy

Kornum, Birgitte R.; Kawashima, Minae; Faraco, Juliette; Ling Lin; Rico, Thomas J.; Hesselson, Stephanie; Axtell, Robert C.; Kuipers, Hedwich; Weiner, Karin; Hamacher, Alexandra; Kassack, Matthias U.; Fang Han; Knudsen, Stine; Jing Li; Xiaosong Dong; Winkelmann8,9,10, Juliane; Plazzi, Giuseppe; Nevsimalova, Sona; Seung-Chul Hong; Honda, Yutaka
January 2011
Nature Genetics;Jan2011, Vol. 43 Issue 1, p66
Academic Journal
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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