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Narcolepsy is strongly associated with the T-cell receptor alpha locus

2009; Nature Portfolio; Volume: 41; Issue: 6 Linguagem: Inglês

10.1038/ng.372

1546-1718

Joachim Hallmayer, Juliette Faraco, Ling Lin, Stephanie Hesselson, Juliane Winkelmann, Minae Kawashima, Geert Mayer, Giuseppe Plazzi, Soňa Nevšímalová, Patrice Bourgin, Seung‐Chul Hong, Yutaka Honda, Makoto Honda, Birgit Högl, W.T. Longstreth, Jacques Montplaisir, David Kemlink, Mali Einen, Justin Chen, Stacy L. Musone, Matthew Akana, Taku Miyagawa, Jubao Duan, Alex Désautels, Christine Erhardt, Per Egil Hesla, Francesca Poli, Birgit Frauscher, Jong‐Hyun Jeong, Sung-Pil Lee, Thanh G.N. Ton, Mark Kvale, Libor Kolesár, Marie Dobrovolná, Gerald T. Nepom, D. Salomon, H‐Erich Wichmann, Guy A. Rouleau, Christian Gieger, Douglas F. Levinson, Pablo V. Gejman, Thomas Meitinger, Terry Young, Paul E. Peppard, Katsushi Tokunaga, Pui‐Yan Kwok, Neil Risch, Emmanuel Mignot,

Cholesterol and Lipid Metabolism

Narcolepsy with cataplexy, characterized by sleepiness and rapid onset into REM sleep, affects 1 in 2,000 individuals. Narcolepsy was first shown to be tightly associated with HLA-DR2 (ref. 3) and later sublocalized to DQB1*0602 (ref. 4). Following studies in dogs and mice, a 95% loss of hypocretin-producing cells in postmortem hypothalami from narcoleptic individuals was reported. Using genome-wide association (GWA) in Caucasians with replication in three ethnic groups, we found association between narcolepsy and polymorphisms in the TRA@ (T-cell receptor alpha) locus, with highest significance at rs1154155 (average allelic odds ratio 1.69, genotypic odds ratios 1.94 and 2.55, P < 10(-21), 1,830 cases, 2,164 controls). This is the first documented genetic involvement of the TRA@ locus, encoding the major receptor for HLA-peptide presentation, in any disease. It is still unclear how specific HLA alleles confer susceptibility to over 100 HLA-associated disorders; thus, narcolepsy will provide new insights on how HLA-TCR interactions contribute to organ-specific autoimmune targeting and may serve as a model for over 100 other HLA-associated disorders.