Abstract
Growing evidence supports the hypothesis that narcolepsy with cataplexy is an autoimmune disease. Using genome-wide association (GWA) in narcolepsy patients versus controls, with replication and fine mapping across three ethnic groups (3406 individuals of European ancestry, 2414 Asians, and 302 African Americans), we found a novel association between SNP rs2305795 in the 3′UTR of the purinergic receptor subtype 2Y11 (P2RY11) gene and narcolepsy (p(Mantel Haenszel)=6.1×10-10; odds ratio 1.28; n=5689). The disease-associated allele is correlated with a 3-fold lower expression of P2RY11 in CD8+ T lymphocytes (p=0.003) and natural killer (NK) cells (p=0.031) but not in other peripheral blood mononuclear cell (PBMC) types. The low expression variant is also associated with decreased P2RY11 mediated resistance to adenosine triphosphate (ATP) induced cell death in T lymphocytes (p=0.0007) and NK 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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