The purinergic receptor P2Y<sub>11</sub> is associated with narcolepsy in genome-wide association studies, and P2RY11 sequencing has further revealed eight rare missense mutations associated with the disease.
Six of the eight narcolepsy-associated P2Y11 mutations resulted in significant functional deficits in P2Y11 signalling through both Ca2+ and cAMP signalling pathways.
Reported susceptibility SNPs for narcolepsy in the Japanese population, CPT1B (carnitine palmitoyltransferase 1B), TRA@ (T-cell receptor alpha) and P2RY11 (purinergic receptor P2Y, G-protein coupled, 11), were found to explain 0.8% of narcolepsy onset (P<sub>whole genome without HLA-DQB1*06:02</sub>=9.74 × 10<sup>-2</sup>).
Genome-wide association studies have strengthened the association between narcolepsy and immune system gene polymorphisms, including the identification of polymorphisms in the T cell receptor alpha locus, TNFSF4 (also called OX40L), Cathepsin H (CTSH) the purinergic receptor P2RY11, and the DNA methyltransferase DNMT1.
Genome-wide association analysis shows a strong association between narcolepsy and polymorphisms in the TCRα locus and weaker associations within TNFSF4 (also called OX40L), Cathepsin H and the P2RY11-DNMT1 (purinergic receptor subtype P2Y11 to DNMT1, a DNA methytransferase) loci, suggesting an autoimmune basis.
Genome wide analysis of narcolepsy in China implicates novel immune loci and reveals changes in association prior to versus after the 2009 H1N1 influenza pandemic.
Chinese narcolepsy was strongly and dose dependently associated with TCRA (rs1154155C) and P2RY11 (rs2305795A) but not CPT1B/CHKB (rs5770917C) polymorphisms.
These results identify P2RY11 as an important regulator of immune-cell survival, with possible implications in narcolepsy and other autoimmune diseases.
These results identify P2RY11 as an important regulator of immune-cell survival, with possible implications in narcolepsy and other autoimmune diseases.